Drug-containing implants and methods of use thereof

ABSTRACT

The present invention provides implants comprising a therapeutic drug and a polymer containing polylactic acid (PLA) and optionally polyglycolic acid (PGA). The present invention also provides methods of maintaining a therapeutic level of a drug in a subject, releasing a therapeutic drug at a substantially linear rate, and treating schizophrenia and other diseases and disorders, utilizing implants of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of PCT InternationalApplication No. PCT/US05/00884, International Filing Date Jan. 12, 2005,which is hereby incorporated in their entirety by reference herein andwhich also claims priority to U.S. Provisional Patent Applications60/535,908 and 60/616,322, filed Jan. 12, 2004 and Oct. 6, 2004,respectively.

FIELD OF INVENTION

The present invention provides implants comprising a therapeutic drugand a polymer containing polylactic acid (PLA) and optionallypolyglycolic acid (PGA). The present invention also provides methods ofmaintaining a therapeutic level of a drug in a subject, releasing atherapeutic drug at a substantially linear rate, and treatingschizophrenia and other diseases and disorders, utilizing implants ofthe present invention.

BACKGROUND OF THE INVENTION

Medication noncompliance is the highest determinant of relapse inschizophrenia. Therefore, a therapy method that helps patients remain onmedication for extended periods would substantially improve clinicaloutcomes. Current methods of administering anti-schizophrenia medication(e.g. risperidone) provide dosing for one month or less. Thus, methodsof providing therapeutic levels of risperidone and other medications areneeded in the art.

SUMMARY OF THE INVENTION

The present invention provides implants comprising a therapeutic drugand a polymer containing polylactic acid (PLA) and optionallypolyglycolic acid (PGA). The present invention also provides methods ofmaintaining a therapeutic level of a drug in a subject, releasing atherapeutic drug at a substantially linear rate, and treatingschizophrenia and other diseases and disorders, utilizing implants ofthe present invention.

In one embodiment, the present invention provides a biodegradableimplant having (a) a therapeutic drug present in an amount of 10%-60% bymass, relative to the mass of the implant; and (b) a polymer present inan amount of 40%-70% by mass, relative to the mass of the implant, thepolymer comprising PLA and optionally PGA in a PLA:PGA molar ratiobetween 50:50 and 100:0.

In another embodiment, the present invention provides a method formaintaining a therapeutic level of a drug in a subject for a period ofat least about 4 months, comprising administering to the subject a setof biodegradable implants, the set of biodegradable implants consistingof one or more individual biodegradable implants having (a) atherapeutic drug present in an amount of 10%-60% by mass, relative tothe mass of the implant; and (b) a polymer present in an amount of40%-70% by mass, relative to the mass of the implant, the polymercomprising PLA and optionally PGA in a PLA:PGA molarratio between 50:50and 100:0 and wherein the individual biodegradable implants, if morethan one in number, do not differ substantially from one another intheir PLA:PGA molar ratio, thereby maintaining a therapeutic level of adrug in a subject for a period of at least about 4 months.

In another embodiment, the present invention provides a method formaintaining a therapeutic level of a drug in a subject for a period ofat least about one year, comprising (1) administering to the subject aninitial set of biodegradable implants, wherein the initial set ofbiodegradable implants consists of one or more individual biodegradableimplants having (a) a therapeutic drug present in an amount of 10%-60%by mass, relative to the mass of the implant; and (b) a polymer presentin an amount of 40%-70% by mass, relative to the mass of the implant,the polymer comprising PLA and optionally PGA in a PLA:PGA molar ratiobetween 50:50 and 100:0; and (2) administering to the subject amaintenance set of one or more biodegradable implants to the subjectnear the point of peak release of the initial set of biodegradableimplants, wherein the maintenance set of biodegradable implants consistsof additional individual biodegradable implants equivalent in thePLA:PGA molar ratio to the individual biodegradable implants in theinitial set of biodegradable implants. The individual biodegradableimplants of the initial set, if more than one in number, do not differsubstantially from one another in their PLA:PGA molar ratio, therebymaintaining a therapeutic level of a drug in a subject for a period ofat least about one year.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: Longitudinal detection of haloperidol levels for 443 days inprimates as a result of implants.

FIG. 2A) Placement of implants during rabbit surgery. A tethered implant(white arrow) is shown. The incision was enlarged to enable aphotograph. B) Necropsy in rabbits showing a degraded implant (blackarrow) at the tethering location between two hemostats. No fibrosis wasobserved upon implant removal. Scale bar=20 mm in both images

FIG. 3. Haloperidol serum concentration from polymer implants in rabbit.Each panel displays the mean±SEM for 5 animals. A) Multiple-polymersystem, B) Single-polymer system. Each set of data is shown with atrendline to illustrate the pattern of the serum concentration overtime.

FIG. 4: Cumulative in vitro concentration from disc & rod-shapedimplants. Each point represents the mean for 3 replicates of discs orrods.

FIG. 5. Stability of risperidone in physiological aqueous solution. A.Amount of remaining risperidone vs. time. The y-intercept is 10.42 forHPLC and 10.23 mg for UV spectrophotometry. Similarly, the slope of thelinear trendline for HPLC is 0.01 and 0.00 for UV spectrophotometry. B)Values for the positive control solution in A, as well as samples in thesurface area to volume ratio study (FIG. 6B) were analyzed and comparedusing HPLC and UV spectrophotometry. The correlation coefficient forthese methods is 0.99 (182 samples), showing that UV spectrophotometryis an accurate measure of drug level in an in vitro solution.

FIG. 6. In vitro risperidone release varies with polymer composition andSA:V ratio: A) Polymer composition—Cumulative in vitro risperidonerelease from 20% load implants containing 50:50, 65:35, or 75:25 PLGA.Data are expressed as cumulative % total release over time. Each pointrepresents the mean±standard error of the mean (SEM) of 3 implants. Fullrelease occurred at about 40, 80 & 120 days, respectively. B) SA tovolume ratio—Rods with the smaller radius, and hence larger SA:V ratio(circles) exhibited faster in vitro release than rods with larger radius(triangles), as evidenced by higher cumulative concentration between 28and 44 days. Points represent mean±SEM from 4 rods. Data were analyzedwith HPLC and UV spectrophotometry, which produced identical results, asin FIG. 5.

FIG. 7. In vitro cumulative risperidone release from implants containing85:15 PLGA with 10, 20, 30, 40, 50 or 60% drug load by weight. A)Cumulative mass of risperidone in the in vitro solution (mean±SEM). B)The pattern for the 40% risperidone implants is shown alone for clarity.The trendline, which has a correlation coefficient of 0.99, is includedto illustrate the pattern. C) Cumulative mass released from 30, 40, 50,and 60% risperidone implants is expressed as a percentage of the totaldrug to facilitate comparison of the pattern of release as a function ofdrug load. The mean value for each type of implant is also depicted.Trendlines for each of these 4 implants had correlation coefficients(R²) of 0.99. 10% and 20% curves were omitted to increase visibility ofoverlapping lines. D) The 40% drug load group is shown alone forincreased clarity.

FIG. 8. Risperidone implants increase PPI but not startle. Risperidoneimplants increased PPI (p=0.052) without a significant change in startleat 14 and 21 days post implantation.

FIG. 9. Risperidone implants increase the P20 and blockamphetamine-induced disruption of the N40 evoked potentials. A)Risperidone implants increased P20 amplitude in C57BL/6J mice (p=0.03)and attenuated amphetamine reduction of N40 (p=0.02).

FIG. 10. Amount of drug released (normalized to the total amount) as afunction of time for different drugs. Although all release profilesfollow a similar S shape, the rates were quite different, both in theregion of initial release, the slope of the constant release zone (whereΔƒ/Δt is constant) and the characteristic time for full release (ƒ=1).

FIG. 11. Fit of the haloperidol (A) and ibuprofene (B) data to the modelpresented in equation 4, using the fit parameters D and k: For (A) k isapproximately 0.1 (1/days) and D is 0.045. For (B) k is approximately0.164 (1/days) and D is 0.051.

FIG. 12. Relationship between maximal solubility of drugs in water after14 days (in mg/mL) and D, the diffusion coefficient of water into thepolymer/drug complex, as calculated from fit of the data in FIG. 10 toequation 4. D is proportional to solubility to the power of 5.3.

FIG. 13: Model for continuous delivery from biodegradable implants: A)Pattern of serum concentration that results from one or moresingle-polymer implants. Trendlines represent the drug release pattern.B) Superimposed profiles for each of 4 implantations of thesingle-polymer implant system. Re-implantation for this polymer-drugcombination is performed every 6 months. C) The total serumconcentration that results from individual overlapping implantations(dashed lines) is shown with a sold line. Levels oscillate slightly, butremain within the target range for as long as implantations occur nearthe time of peak concentration for a given material. Arrows markimplantations in all panels.

FIG. 14. Risperidone serum concentration resulting from amultiple-polymer risperidone implant system. A) Serum concentrationresulting from a set of 4 rapid-release implants. B) Serum concentrationresulting from a 5-polymer system, in which 4 rapidly degrading polymers(“starter set”) are combined with 1 longer lasting polymer that isre-implanted every 6 months as a maintenance set. Overall drugconcentration is represented with the solid line, and release profilesfrom individual polymers are represented by dashed lines. Target druglevels are attained in approximately 1 week, with small oscillationsaround the target concentration thereafter.

FIG. 15. Insertion of rod-shaped implants. A) Insertion of a 1-cmrod-shaped implant through a 4-mm hole. Insert illustrates a 1-cmimplant prior to insertion. B) Implant shown in situ after closing witha single stitch. C) Mouse 10 minutes later in home cage without signs ofdistress.

FIG. 16. Representative cross-sectional shapes of rods, disks, andcylinders of implants of the present invention (a non-exhaustivelisting).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides implants comprising a therapeutic drugand a

polymer containing polylactic acid (PLA) and optionally polyglycolicacid (PGA). The present invention also provides methods of maintaining atherapeutic level of a drug in a subject, releasing a therapeutic drugat a substantially linear rate, and treating schizophrenia and otherdiseases and disorders, utilizing implants of the present invention.

In one embodiment, the present invention provides an implantable, longterm delivery system for improving medication adherence in disordersassociated with a likelihood of non-compliance. The delivery system, inone embodiment, includes a therapeutic drug in an implantable, rodshaped structure and improves medication adherence in subjects havingdisorders associated with a likelihood of non-compliance.

The term “implantable” includes, in various embodiments, compositionswhich can be inserted into the subject, e.g., subcutaneously,intramuscularly, etc. In a further embodiment, the implantablecompositions are also removable.

The term “long term” includes, in various embodiments, periods of timegreater than about three months, greater than about four months, greaterthan about five months, greater than about six months, greater thanabout seven months, greater than about eight months, greater than aboutnine months, greater than about ten months, greater than about elevenmonths, greater than about one year or longer.

The term “long term delivery system” includes, in one embodiment,systems which, once administered to the subject, gradually deliver thetarget therapeutic drug to the subject in an effective amount to treatthe disorder associated with a likelihood of non-compliance. The drugmay be delivered, in other embodiments, over a period of greater thanabout three months, greater than about four months, greater than aboutfive months, greater than about six months, greater than about sevenmonths, greater than about eight months, greater than about nine months,greater than about ten months, greater than about eleven months, greaterthan about one year or longer.

The language “improving medication adherence” refers, in one embodiment,to increasing the percentage of time subjects with a disorder associatedwith a likelihood of non-compliance are treated for their disorder withthe target therapeutic drug.

The language “disorder associated with a likelihood of non-compliance”includes, in one embodiment, psychotic disorders, such as schizophrenia,bipolar disorder, dementia, delirium, impulse control disorder,psychotic depression, drug addiction, etc. The language “disorderassociated with a likelihood of non-compliance” refers, in oneembodiment, to disorders which have a high rate of subjectnon-compliance. It includes, in another embodiment, disorders where thedisorder affects the subject's judgment or mental capacity. The languageincludes, in another embodiment, disorders with a low rate (e.g., invarious embodiments, below 90%, below 80%, below 70%, below 60%, below50%, below 40% and below 30%) of subject compliance.

The term “therapeutic drug” includes, in one embodiment, drugs used totreat disorders associated with a likelihood of non-compliance. Inanother embodiment, the therapeutic drug is an anti-depressant. Inanother embodiment, the therapeutic drug is an antianxiety agent. Inanother embodiment, the therapeutic drug is an anti-psychotic agent. Inanother embodiment, the target therapeutic drug is a birth control drug.

In another embodiment, the present invention provides a biodegradableimplant having (a) a therapeutic drug present in an amount of 10%-60% bymass, relative to the mass of the implant; and (b) a polymer present inan amount of 40%-70% by mass, relative to the mass of the implant, thepolymer comprising PLA and optionally PGA in a PLA:PGA molar ratiobetween 50:50 and 100:0.

The term “biodegradable,” as used herein, refers, in one embodiment, toa material that is degraded in a biological environment. In anotherembodiment, “biodegradable” refers to a material that has a finitehalf-life in a biological environment. In another embodiment,“biodegradable” refers to a material that has a measurable half-life ina biological environment. In another embodiment, “biodegradable” refersto a material that is degraded inside a living organism. In anotherembodiment, “biodegradable” refers to a material that has a finitehalf-life inside a living organism. In another embodiment,“biodegradable” refers to a material that has a measurable half-lifeinside a living organism. In another embodiment, the term“biodegradable” is equivalent to the term “bioerodible.”

In one embodiment, the half-life is 1 month or less. In anotherembodiment, the half-life is 2 months or less. In another embodiment,the half-life is 3 months or less. In another embodiment, the half-lifeis 4 months or less. In another embodiment, the half-life is 5 months orless. In another embodiment, the half-life is 6 months or less. Inanother embodiment, the half-life is 8 months or less. In anotherembodiment, the half-life is 10 months or less. In another embodiment,the half-life is one year or less. In another embodiment, the half-lifeis 1.5 years or less. In another embodiment, the half-life is 2 years orless. In another embodiment, the half-life is 3 years or less. Inanother embodiment, the half-life is 4 years or less. In anotherembodiment, the half-life is 5 years or less. In another embodiment, thehalf-life is 7 years or less. In another embodiment, the half-life is 10years or less. Each possibility represents a separate embodiment of thepresent invention.

“Polymer” refers, in one embodiment, to a macromolecule composed ofindividual units, or monomers. In another embodiment, the polymer is abranched polymer. In another embodiment, the polymer is a linearpolymer. In another embodiment, the polymer is a cross-linked polymer.In another embodiment, the polymer is any other type of polymer known inthe art. Each possibility represents a separate embodiment of thepresent invention.

PLA:PGA polymers contain PLA and PGA monomers, while PLA polymerscontain only PLA monomers. Methods for use and synthesis of PLA polymersand PLA:PGA polymers are well known in the art, and are described, forexample, in Fukushima K et al (Macromol Biosci 5(1): 21-9, 2005);Saulnier B et al (Macromol Biosci 15; 4(3): 232-7, 2004); and Park S Jet al (J Colloid Interface Sci 271(2): 336-41, 2004). Each methodrepresents a separate embodiment of the present invention.

In one embodiment, an implant of methods and compositions of the presentinvention is rod shaped. As provided herein, results of the presentinvention show that rod-shaped implants as well as disk-shaped implantscan be used to provide extended delivery of risperidone and other drugs.In another embodiment, the implant is disc shaped. In anotherembodiment, implant is cylindrical. In another embodiment, implant is asheet. In another embodiment, the implant is any shape suitable forretention in a body tissue. (e.g. subcutaneous tissue). In anotherembodiment, the implant is any shape suitable for structural stabilityin the subcutaneous space. In another embodiment, the implant is anyshape suitable for tolerability in the subcutaneous space. In anotherembodiment, the implant is any other shape known in the art.

“Rod-shaped” refers, in one embodiment, to a shape whose cross-sectionis substantially round, and whose length is at least twice the diameterof the cross-section. In another embodiment, the cross-sectional shapeis any other cross-sectional shape of the present invention. In anotherembodiment, the length is at least as great as the diameter of thecross-section. In another embodiment, the length is at least 1.1 timesthe diameter of the cross-section. In another embodiment, the length isat least 1.2 times the diameter. In another embodiment, the length is atleast 1.3 times the diameter. In another embodiment, the length is atleast 1.4 times the diameter. In another embodiment, the length is atleast 1.5 times the diameter. In another embodiment, the length is atleast 1.6 times the diameter. In another embodiment, the length is atleast 1.7 times the diameter. In another embodiment, the length is atleast 1.8 times the diameter. In another embodiment, the length is atleast 1.9 times the diameter. In another embodiment, the length is atleast 2.2 times the diameter. In another embodiment, the length is atleast 2.5 times the diameter. In another embodiment, the length is atleast 3 times the diameter. In another embodiment, the length is atleast 4 times the diameter. Each possibility represents a separateembodiment of the present invention.

“Disk-shaped” refers, in one embodiment, to a substantially round, flatshape. In another embodiment, the shape is oval, square, rectangular,etc. The thickness is, in one embodiment, less than the diameter of thecircle, oval, etc. In another embodiment, the thickness is less than 0.9times the diameter of the shape. In another embodiment, the thickness isless than 0.8 times the diameter. In another embodiment, the thicknessis less than 0.7 times the diameter. In another embodiment, thethickness is less than 0.6 times the diameter. In another embodiment,the thickness is less than 0.5 times the diameter. In anotherembodiment, the thickness is less than 0.4 times the diameter. Inanother embodiment, the thickness is less than 0.3 times the diameter.In another embodiment, the thickness is less than 0.2 times thediameter. In another embodiment, the thickness is less than 0.1 timesthe diameter. Each possibility represents a separate embodiment of thepresent invention.

In one embodiment, the rods, disks, and cylinders referred to hereinhave a substantially circular cross-sectional shape. In anotherembodiment, the cross-sectional shape is ellipsoidal. In anotherembodiment, the ellipsoidal shape need not be round at the edges. Inanother embodiment, the cross-sectional shape is any shape in FIG. 16.In another embodiment, the cross-sectional shape is any other shapeknown in the art. Because the present invention has shown that releaserate of drug from an implant is proportional to its surface area, theshape of the implant can be modified, in one embodiment, to conferthereupon desirable characteristics without altering the release rate,provided that the surface area remains constant. Similarly, the presentinvention has shown that duration of release of drug from an implant isproportional to its SA:V ratio; thus, the shape of the implant can bemodified, in one embodiment, to confer thereupon desirablecharacteristics without altering the duration of release, provided thatthe SA:V ratio remains constant. Each shape represents a separateembodiment of the present invention.

In another embodiment, the cross-sectional area is substantiallyconstant over the length of the rods, disks, and cylinders of thepresent invention. In another embodiment, the cross-sectional area isnot constant. In another embodiment, the cross-sectional dimensions aresubstantially constant over the length of the rods, disks, and cylindersof the present invention. In another embodiment, the cross-sectionaldimensions are not constant. Each possibility represents a separateembodiment of the present invention.

In another embodiment, an implant of the present invention has arectangular cross-sectional shape. In another embodiment, thecross-sectional shape is a square. In another embodiment, thecross-sectional shape is any other shape known in the art.

In another embodiment, the implant is monolithic. In another embodiment,the implant is composed of several (10 or fewer) smaller components thatare fused together. In another embodiment, the components are linkedtogether. Each possibility represents a separate embodiment of thepresent invention.

Each of the above overall shapes and cross-sectional shapes represents aseparate embodiment of the present invention.

Methods of insertion of implants are well known in the art. In oneembodiment, implants are inserted through a minimally invasive approach,using a surgical instrument known as a “trochar.” In another embodiment,the implants are inserted utilizing a procedure and tool set (trocharand obdurator) similar to those used for Norplant (Townsend S “Insertionand removal of Norplant” Netw Fr 6: 8-9, 1991). In another embodiment,rod-shaped implants provide an advantage due to their ease ofimplantation and lack of subsequent discomfort (FIG. 15). In anotherembodiment, an advantage of rod-shaped implants is the small incisionsrequired for their insertion; e.g. in various embodiments, about 2 mm, 3mm, 4 mm, 5 mm, 6 mm, or 7 mm. In another embodiment, implants providean advantage due to their ability to be implanted on an outpatientbasis. The incision site is closed, in another embodiment, with either asingle stitch or steristrips (FIG. 15). In another embodiment, theimplant is inserted by any other surgical method known in the art. Eachmethod represents a separate embodiment of the present invention.

In another embodiment, implants of the present invention provide anadvantage due to their lack of necessity of the subject receivinginjections every few weeks, thus increasing patient compliance. Inanother embodiment, the advantage of the implants is due to theresulting increased patient autonomy. In another embodiment, theadvantage of the implants is due to their lack of irritation at the siteof administration.

In another embodiment, the advantage of the implants is due to theirstability at body temperature for the delivery period.

In another embodiment, the advantage of the implants is due to abilityto completely erode, thus exhibiting a lack of necessity of removingresidual material. In one embodiment, the erosion is primarily surfaceerosion. In another embodiment, the erosion is primarily bulk erosion.In another embodiment, the erosion is a combination of substantialamounts of surface erosion and bulk erosion. Each possibility representsa separate embodiment of the present invention.

In another embodiment, an implant of methods and compositions of thepresent is tethered (FIG. 2) to assist in locating it and, if necessary,removing it. As provided herein, the removal process has beensuccessfully tested in mice and rats. In another embodiment, followingpalpation of the implant, a small incision is made and residual materialfrom the implant is retrieved using forceps.

In another embodiment, the implant is removable. “Removable” refers, inone embodiment, to the ability of the implant to be removed by surgicalor other means. In another embodiment, “removable” refers to the abilityof the remains of the implant to be removed. In another embodiment,“removable” refers to the ability of most of the remains of the implantto be removed. In one embodiment, the implant is removed due to anadverse reaction to the medication therein. In another embodiment, theimplant is removed due to a decision by the physician. In anotherembodiment, the implant is removed due to a decision by the patient. Inanother embodiment, the implant is removed due to an overdose ofmedication. In another embodiment, the implant is removed due to anyother reason for which the course of treatment is desired to be halted.Each possibility represents a separate embodiment of the presentinvention.

In another embodiment, a polymer utilized in methods and compositions ofthe present invention comprises PLA but not PGA. In another embodiment,the polymer comprises PLA and PGA. In another embodiment, the polymerconsists of PLA alone. In another embodiment, the polymer consists ofPLA and PGA. Each possibility represents a separate embodiment of thepresent invention.

In another embodiment, the drug load of an implant of methods andcompositions of the present invention is between 30-60%. As providedherein (Example 7), results of the present invention have demonstratedthe efficacy of particular drug load ranges of biodegradable implants.“Drug load” refers, in one embodiment, to the amount of drug in theimplant as a percentage by mass. In another embodiment, “drug load”refers to the percentage by weight of the drug. In another embodiment,e.g. if other materials are present in the implant besides thetherapeutic drug and the polymer, the drug load is calculated withoutconsidering the other materials. Each possibility represents a separateembodiment of the present invention.

In another embodiment, the drug load is between about 40-50%. In anotherembodiment, the drug load is from 1-5%. In another embodiment, the drugload is from 2-5%. In another embodiment, the drug load is from 5-10%.In another embodiment, the drug load is from 10-15%. In anotherembodiment, the drug load is from 15-20%. In another embodiment, thedrug load is from 20-25%. In another embodiment, the drug load is from25-30%. In another embodiment, the drug load is from 30-35%. In anotherembodiment, the drug load is from 35-40%. In another embodiment, thedrug load is from 40-45%. In another embodiment, the drug load is from45-50%. In another embodiment, the drug load is from 50-55%. In anotherembodiment, the drug load is from 55-60%. In another embodiment, thedrug load is from 60-65%. In another embodiment, the drug load is from65-70%. In another embodiment, the drug load is from 70-75%. In anotherembodiment, the drug load is from 75-80%. In another embodiment, thedrug load is from 80-85%. In another embodiment, the drug load is from85-90%. In another embodiment, the drug load is from 90-95%. In anotherembodiment, the drug load is from 95-99%. In another embodiment, thedrug load is from 5-15%. In another embodiment, the drug load is from10-20%. In another embodiment, the drug load is from 15-25%. In anotherembodiment, the drug load is from 20-30%. In another embodiment, thedrug load is from 25-35%. In another embodiment, the drug load is from30-40%. In another embodiment, the drug load is from 35-45%. In anotherembodiment, the drug load is from 45-55%. In another embodiment, thedrug load is from 50-60%. In another embodiment, the drug load is from55-65%. In another embodiment, the drug load is from 60-70%. In anotherembodiment, the drug load is from 70-80%. In another embodiment, thedrug load is from 80-90%. In another embodiment, the drug load is from90-99%. In another embodiment, the drug load is from 5-20%. In anotherembodiment, the drug load is from 10-25%. In another embodiment, thedrug load is from 15-30%. In another embodiment, the drug load is from20-35%. In another embodiment, the drug load is from 25-40%. In anotherembodiment, the drug load is from 30-45%. In another embodiment, thedrug load is from 35-50%. In another embodiment, the drug load is from40-55%. In another embodiment, the drug load is from 45-60%. In anotherembodiment, the drug load is from 50-65%. In another embodiment, thedrug load is from 55-70%. In another embodiment, the drug load is from5-25%. In another embodiment, the drug load is from 10-30%. In anotherembodiment, the drug load is from 15-35%. In another embodiment, thedrug load is from 20-40%. In another embodiment, the drug load is from25-45%. In another embodiment, the drug load is from 30-50%. In anotherembodiment, the drug load is from 35-55%. In another embodiment, thedrug load is from 40-60%. In another embodiment, the drug load is from45-65%. In another embodiment, the drug load is from 50-70%.

In another embodiment, the drug load is 2%. In another embodiment, thedrug load is 3%. In another embodiment, the drug load is 5%. In anotherembodiment, the drug load is 6%. In another embodiment, the drug load is8%. In another embodiment, the drug load is 10%. In another embodiment,the drug load is 12%. In another embodiment, the drug load is 14%. Inanother embodiment, the drug load is 16%. In another embodiment, thedrug load is 18%. In another embodiment, the drug load is 20%. Inanother embodiment, the drug load is 22%. In another embodiment, thedrug load is 24%. In another embodiment, the drug load is 26%. Inanother embodiment, the drug load is 28%. In another embodiment, thedrug load is 30%. In another embodiment, the drug load is 32%. Inanother embodiment, the drug load is 34%. In another embodiment, thedrug load is 36%. In another embodiment, the drug load is 38%. Inanother embodiment, the drug load is 40%. In another embodiment, thedrug load is 42%. In another embodiment, the drug load is 44%. Inanother embodiment, the drug load is 46%. In another embodiment, thedrug load is 48%. In another embodiment, the drug load is 50%. Inanother embodiment, the drug load is 52%. In another embodiment, thedrug load is 54%. In another embodiment, the drug load is 56%. Inanother embodiment, the drug load is 58%. In another embodiment, thedrug load is 60%. In another embodiment, the drug load is 65%. Inanother embodiment, the drug load is 70%. Each drug load represents aseparate embodiment of the present invention.

Numerical and other ranges used to describe methods and compositions ofthe present invention are understood to be inclusive of the boundaryvalues. Each value or combination of values within the range representsa separate embodiment of the present invention.

A “therapeutic drug” is, in one embodiment, any drug or compound thatexhibits any type of therapeutic or beneficial effect when administeredto a subject. In another embodiment, the therapeutic drug contained inan implant of methods and compositions of the present invention isrisperidone. In another embodiment the therapeutic drug is9-OH-risperidone. In another embodiment, the therapeutic drug isthiothixene. In another embodiment, the therapeutic drug is haloperidol.In another embodiment, the therapeutic drug is hydrochlorothiazide(HCTZ). In another embodiment, the therapeutic drug is corticosterone.In another embodiment, the therapeutic drug is ibuprofen. In anotherembodiment, the therapeutic drug is aspirin. In another embodiment, thetherapeutic drug is pimozide. In another embodiment, the therapeuticdrug is aripiprazole. In another embodiment, the therapeutic drug isolanzapine. In another embodiment, the therapeutic drug is donepezil. Inanother embodiment, the therapeutic drug is any other therapeutic drugknown in the art.

PLA polymers and PLA:PGA polymers exhibit an advantage, in oneembodiment, that drugs need not be chemically modified beforeincorporation therein, rather, they need only be mechanically mixed intothe polymeric matrix. Thus, a wide variety of therapeutic agents can beincorporated.

In other embodiments, the therapeutic drug is a dopaminergic agent. Inone embodiment, the dopaminergic agent is an agonist. In one embodiment,the dopaminergic agent is an antagonist. In one embodiment, thedopaminergic agent is a partial agonist. In one embodiment, thedopaminergic agent is a monoamine reuptake inhibitor. In one embodiment,the dopaminergic agent is a monoamine uptake facilitators.

In other embodiments, the therapeutic drug is one of the followingdrugs, or belongs to one of the following classes: antihypertensives,antidepressants, antianxiety agents, anticlotting agents,anticonvulsants, blood glucose-lowering agents, decongestants,antihistamines, antitussives, anti-inflammatories, antipsychotic agents,cognitive enhancers, cholesterol-reducing agents, antiobesity agents,autoimmune disorder agents, anti-impotence agents, antibacterial andantifungal agents, hypnotic agents, anti-Parkinsonism agents,antibiotics, antiviral agents, anti-neoplastics, barbituates, sedatives,nutritional agents, beta blockers, emetics, anti-emetics, diuretics,anticoagulants, cardiotonics, androgens, corticoids, anabolic agents,growth hormone secretagogues, anti-infective agents, coronaryvasodilators, carbonic anhydrase inhibitors, antiprotozoals,gastrointestinal agents, serotonin antagonists, anesthetics,hypoglycemic agents, anti-Alzheimer's Disease agents, anti-ulcer agents,platelet inhibitors glycogen phosphorylase inhibitors, andphosphodiesterase inhibitors.

In other embodiments, the therapeutic drug is one of the followingdrugs: chlorpropamide, fluconazole, atorvastatin calcium, hydroxyzinehydrochloride, doxepin hydrochloride, amlodipine besylate, piroxicam,celicoxib, valdicoxib, carbenicillin indanyl sodium, bacampicillinhydrochloride, troleandomycin, and doxycycline hyclate.

In other embodiments, the therapeutic drug is one of the followingdrugs, or belongs to one of the following classes: platinum compounds(e.g., spiroplatin, cisplatin, and carboplatin), methotrexate,fluorouracil, adriamycin, mitomycin, ansamitocin, bleomycin, cytosinearabinoside, arabinosyl adenine, mercaptopolylysine, vincristine,busulfan, chlorambucil, melphalan (e.g., PAM, L-PAM or phenylalaninemustard), mercaptopurine, mitotane, procarbazine hydrochloridedactinomycin (actinomycin D), daunorubicin hydrochloride, doxorubicinhydrochloride, paclitaxel and other taxenes, rapamycin, manumycin A,TNP-470, plicamycin (mithramycin), aminoglutethimide, estramustinephosphate sodium, flutamide, leuprolide acetate, megestrol acetate,tamoxifen citrate, testolactone, trilostane, arnsacrine (m-AMSA),asparaginase (L-asparaginase) Erwina asparaginase, interferon.alpha.-2a, interferon .alpha.-2b, teniposide (VM-26), vinblastinesulfate (VLB), vincristine sulfate, bleomycin sulfate, hydroxyurea,procarbazine, and dacarbazine; mitotic inhibitors, e.g. etoposide,coichicine, and the vinca alkaloids, radiopharmaceuticals, e.g.radioactive iodine and phosphorus products; hormones, e.g. progestins,estrogens and antiestrogens; anti-helmintics, antimalarials, andantituberculosis drugs; biologicals, e.g. immune serums, antitoxins andantivenoms; rabies prophylaxis products; bacterial vaccines; viralvaccines; respiratory products, e.g. xanthine derivatives theophyllineand aminophylline; thyroid agents, e.g. iodine products and anti-thyroidagents; cardiovascular products including chelating agents and mercurialdiuretics and cardiac glycosides; glucagon; blood products, e.g.parenteral iron, hemin, hematoporphyrins and their derivatives;biological response modifiers, e.g. muramyldipeptide, muramyltripeptide,microbial cell wall components, lymphokines (e.g., bacterial endotoxin,e.g. lipopolysaccharide, macrophage activation factor), sub-units ofbacteria (such as Mycobacteria, Corynebacteria), the synthetic dipeptideN-acetyl-murarnyl-L-alanyl-D-isoglutamine; anti-fungal agents, e.g.ketoconazole, nystatin, griseofulvin, flucytosine (5-fc), miconazole,amphotericin B, ricin, cyclosporins, and β-lactam antibiotics (e.g.,sulfazecin); hormones, e.g. growth hormone, melanocyte stimulatinghormone, estradiol, beclomethasone dipropionate, betamethasone,betamethasone acetate and betamethasone sodium phosphate, vetamethasonedisodium phosphate, vetamethasone sodium phosphate, cortisone acetate,dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate,flunisolide, hydrocortisone, hydrocortisone acetate, hydrocortisonecypionate, hydrocortisone sodium phosphate, hydrocortisone sodiumsuccinate, methylprednisolone, methylprednisolone acetate,methylprednisolone sodium succinate, paramethasone acetate,prednisolone, prednisolone acetate, prednisolone sodium phosphate,prednisolone tebutate, prednisone, triamcinolone, triamcinoloneacetonide, triamcinolone diacetate, triamcinolone hexacetonide,fludrocortisone acetate, oxytocin, vassopressin, and their derivatives;vitamins, e.g. cyanocobalamin neinoic acid, retinoids and derivatives,e.g. retinol palmitate, and .alpha.-tocopherol; peptides, e.g. manganesesuper oxide dismutase; enzymes, e.g. alkaline phosphatase; anti-allergicagents, e.g. amelexanox; anti-coagulation agents, e.g. phenprocoumon andheparin; circulatory drugs, e.g. propranolol; metabolic potentiators,e.g. glutathione; antituberculars, e.g. para-aminosalicylic acid,isoniazid, capreomycin sulfate cycloserine, ethambutol hydrochlorideethionamide, pyrazinamide, rifampin, and streptomycin sulfate;antivirals, e.g. amantadine azidothymidine (AZT, DDI, Foscarnet, orZidovudine), ribavirin and vidarabine monohydrate (adenine arabinoside,ara-A); antianginals, e.g. diltiazem, nifedipine, verapamil, erythritoltetranitrate, isosorbide dinitrate, nitroglycerin (glyceryl trinitrate)and pentaerythritol tetranitrate; anticoagulants, e.g. phenprocoumon,heparin; antibiotics, e.g. dapsone, chloramphenicol, neomycin, cefaclor,cefadroxil, cephalexin, cephradine erythromycin, clindamycin,lincomycin, amoxicillin, ampicillin, bacampicillin, carbenicillin,dicloxacillin, cyclacillin, picloxacillin, hetacillin, methicillin,nafcillin, oxacillin, penicillin including penicillin G and penicillinV, ticarcillin rifampin and tetracycline; antiinflammatories, e.g.diflunisal, ibuprofen, indomethacin, meclofenamate, mefenamic acid,naproxen, oxyphenbutazone, phenylbutazone, piroxicam, sulindac,tolmetin, aspirin and salicylates; antiprotozoans, e.g. chloroquine,hydroxychloroquine, metronidazole, quinine and meglumine antimonate;antirheumatics, e.g. penicillamine; narcotics, e.g. paregoric; opiates,e.g. codeine, heroin, methadone, morphine and opium; cardiac glycosides,e.g. deslanoside, digitoxin, digoxin, digitalin and digitalis;neuromuscular blockers, e.g. atracurium mesylate, gallaminetriethiodide, hexafluorenium bromide, metocurine iodide, pancuroniumbromide, succinylcholine chloride (suxamethonium chloride), tubocurarinechloride and vecuronium bromide; sedatives (hypnotics), e.g.amobarbital, amobarbital sodium, aprobarbital, butabarbital sodium,chloral hydrate, ethchlorvynol, ethinarnate, flurazepam hydrochloride,glutethimide, methotrimeprazine hydrochloride, methyprylon, midazolamhydrochloride, paraldehyde, pentobarbital, pentobarbital sodium,phenobarbital sodium, secobarbital sodium, talbutal, temazepam andtriazolam; local anesthetics, e.g. bupivacaine hydrochloride,chloroprocaine hydrochloride, etidocaine hydrochloride, lidocainehydrochloride, mepivacaine hydrochloride, procaine hydrochloride andtetracaine hydrochloride; general anesthetics, e.g. droperidol,etomidate, fentanyl citrate with droperidol, ketamine hydrochloride,methohexital sodium and thiopental sodium; and radioactive particles orions, e.g. strontium, iodide rhenium and yttrium.

In another embodiment, the therapeutic drug is a metabolite ofrisperidone. In another embodiment, the therapeutic drug is a metaboliteof one of the above drug. In one embodiment, the metabolite is an activemetabolite.

In another embodiment, the therapeutic drug is a drug that is usedchronically.

In another embodiment, the therapeutic drug is a high potency drug.“High potency agent” refers, in one embodiment, to a drug that requiresa low serum concentration to exert a therapeutic effect. In anotherembodiment, “high potency agent” refers to a drug that requires a lowtissue concentration to exert a therapeutic effect. In anotherembodiment, “high potency agent” refers to a drug that requires a lowsystemic concentration to exert a therapeutic effect. Each possibilityrepresents a separate embodiment of the present invention.

In one embodiment, the concentration required for a high potency agentto exert a therapeutic effect is 0.01 mg/kg. In another embodiment, theconcentration is 0.02 mg/kg. In another embodiment, the concentration is0.03 mg/kg. In another embodiment, the concentration is 0.04 mg/kg. Inanother embodiment, the concentration is 0.05 mg/kg. In anotherembodiment, the concentration is 0.06 mg/kg. In another embodiment, theconcentration is 0.07 mg/kg. In another embodiment, the concentration is0.08 mg/kg. In another embodiment, the concentration is 0.09 mg/kg. Inanother embodiment, the concentration is 0.10 mg/kg. In anotherembodiment, the concentration is 0.12 mg/kg. Each definition of “highpotency agent” represents a separate embodiment of the presentinvention.

In one embodiment, the concentration required for a high potency agentto exert a therapeutic effect is 1 nanograms (ng)/ml. In anotherembodiment, the concentration is 1.5 ng/ml. In another embodiment, theconcentration is 2 ng/ml. In another embodiment, the concentration is 3ng/ml. In another embodiment, the concentration is 4 ng/ml. In anotherembodiment, the concentration is 5 ng/ml. In another embodiment, theconcentration is 6 ng/ml. In another embodiment, the concentration is 7ng/ml. In another embodiment, the concentration is 8 ng/ml. In anotherembodiment, the concentration is 9 ng/ml. In another embodiment, theconcentration is 10 ng/ml. In another embodiment, the concentration is12 ng/ml. In another embodiment, the concentration is 15 ng/ml. Inanother embodiment, the concentration is 20 ng/ml. Each definition of“high potency agent” represents a separate embodiment of the presentinvention.

Each therapeutic drug represents a separate embodiment of the presentinvention.

In another embodiment, an implant of methods and compositions of thepresent invention contains a combination of therapeutic drugs. In oneembodiment, the implant contains two therapeutic drugs. In anotherembodiment, the implant contains three therapeutic drugs. In anotherembodiment, the implant contains four therapeutic drugs. In anotherembodiment, the implant contains more than four therapeutic drugs. Inanother embodiment, the implant contains a combination of one of theabove drugs with an additional drug. In another embodiment, the implantcontains a combination of two or more drugs not listed above. In anotherembodiment, the combination of drugs contained in the implant has asynergistic effect. In another embodiment, the combination of drugscontained in the implant has an additive effect. Each possibilityrepresents a separate embodiment of the present invention.

As described above, a wide variety of drugs can be incorporated into PLApolymers and PLA:PGA polymers. Before incorporation, the drug (or“active ingredient”) may be prepared by any method known in the art. Thepreparation of pharmaceutical compositions that contain an activeingredient, for example by mixing, granulating, or tablet-formingprocesses, is well understood in the art. The active therapeuticingredient is mixed, in one embodiment, with excipients that arepharmaceutically acceptable and compatible with the active ingredient.In another embodiment, the active ingredient or one of itsphysiologically tolerated derivatives such as salts, esters, N-oxides,and the like is mixed with additives customary for this purpose, such asvehicles, stabilizers, or inert diluents.

An active component is, in another embodiment, formulated into thecomposition as neutralized pharmaceutically acceptable salt forms.Pharmaceutically acceptable salts include the acid addition salts(formed with the free amino groups of the polypeptide or antibodymolecule), which are formed with inorganic acids such as, for example,hydrochloric or phosphoric acids, or such organic acids as acetic,oxalic, tartaric, mandelic, and the like. Salts formed from the freecarboxyl groups can also be derived from inorganic bases such as, forexample, sodium, potassium, ammonium, calcium, or ferric hydroxides, andsuch organic bases as isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, procaine, and the like.

Each of the above additives, excipients, formulations and methods ofadministration represents a separate embodiment of the presentinvention.

In another embodiment, the PLA:PGA molar ratio of a polymer of methodsand compositions of the present invention is between about 75:25 and100:0. In another embodiment, the ratio is between 85:15 and 100:0. Inanother embodiment, the ratio is from 50:50 and 100:0. In anotherembodiment, the ratio is from 50:50 and 55:45. In another embodiment,the ratio is from 55:15 and 60:40. In another embodiment, the ratio isfrom 60:40 and 65:35. In another embodiment, the ratio is from 65:35 and70:30. In another embodiment, the ratio is from 70:30 and 75:25. Inanother embodiment, the ratio is from 75:25 and 80:20. In anotherembodiment, the ratio is from 80:20 and 85:15. In another embodiment,the ratio is from 85:15 and 90:10. In another embodiment, the ratio isfrom 90:10 and 95:5. In another embodiment, the ratio is from 95:5 and100:0. In another embodiment, the ratio is from 96:4 and 100:0. Inanother embodiment, the ratio is from 97:3 and 100:0. In anotherembodiment, the ratio is from 98:2 and 100:0. In another embodiment, theratio is from 99:1 and 100:0. In another embodiment, the ratio is from50:50 and 60:40. In another embodiment, the ratio is from 55:45 and65:35. In another embodiment, the ratio is from 60:40 and 70:30. Inanother embodiment, the ratio is from 65:35 and 75:25. In anotherembodiment, the ratio is from 70:30 and 80:20. In another embodiment,the ratio is from 75:25 and 85:15. In another embodiment, the ratio isfrom 80:20 and 90:10. In another embodiment, the ratio is from 85:15 and95:5. In another embodiment, the ratio is from 90:10 and 100:0. Inanother embodiment, the ratio is from 50:50 and 65:35. In anotherembodiment, the ratio is from 55:45 and 70:30. In another embodiment,the ratio is from 60:40 and 75:25. In another embodiment, the ratio isfrom 65:35 and 80:20. In another embodiment, the ratio is from 70:30 and85:15. In another embodiment, the ratio is from 75:25 and 90:10. Inanother embodiment, the ratio is from 80:20 and 95:5. In anotherembodiment, the ratio is from 85:15 and 100:0. In another embodiment,the ratio is from 50:50 and 70:30. In another embodiment, the ratio isfrom 55:45 and 75:25. In another embodiment, the ratio is from 60:40 and80:20. In another embodiment, the ratio is from 65:35 and 85:15. Inanother embodiment, the ratio is from 70:30 and 90:10. In anotherembodiment, the ratio is from 75:25 and 95:05. In another embodiment,the ratio is from 80:20 and 100:0. In another embodiment, the ratio isfrom 50:50 and 75:25. In another embodiment, the ratio is from 55:45 and80:20. In another embodiment, the ratio is from 60:40 and 85:15. Inanother embodiment, the ratio is from 65:35 and 90:10. In anotherembodiment, the ratio is from 70:30 and 95:5. In another embodiment, theratio is from 75:25 and 100:0.

In another embodiment, the ratio is 50:50. In another embodiment, theratio is 52:48. In another embodiment, the ratio is 54:46. In anotherembodiment, the ratio is 56:44. In another embodiment, the ratio is58:42. In another embodiment, the ratio is 60:40. In another embodiment,the ratio is 62:38. In another embodiment, the ratio is 64:36. Inanother embodiment, the ratio is 66:34. In another embodiment, the ratiois 68:32. In another embodiment, the ratio is 70:30. In anotherembodiment, the ratio is 72:28. In another embodiment, the ratio is74:26. In another embodiment, the ratio is 76:24. In another embodiment,the ratio is 78:22. In another embodiment, the ratio is 80:20. Inanother embodiment, the ratio is 82:18. In another embodiment, the ratiois 84:16. In another embodiment, the ratio is 86:14. In anotherembodiment, the ratio is 88:12. In another embodiment, the ratio is90:10. In another embodiment, the ratio is 92:8. In another embodiment,the ratio is 94:6. In another embodiment, the ratio is 96:4. In anotherembodiment, the ratio is 97:3. In another embodiment, the ratio is 98:2.In another embodiment, the ratio is 99:1. In another embodiment, theratio is 100:0 (e.g. substantially less than 1% PGA).

As provided herein (Example 5), results of the present invention havedemonstrated the efficacy of particular drug PLA:PGA ratios ofbiodegradable implants. In one embodiment, the PLA:PGA ratio is a molarratio. In another embodiment, the PLA:PGA ratio is a mass ratio. Inanother embodiment, the PLA:PGA ratio is a weight ratio. In anotherembodiment, the PLA:PGA ratio is a volume ratio. Each of the abovePLA:PGA ratios represents a separate embodiment of the presentinvention.

In another embodiment, a polymer of methods and compositions of thepresent invention exhibits an inherent viscosity of between about0.2-0.9 dl/g in chloroform. In another embodiment, the inherentviscosity is from 0.6-0.85 dl/g. In another embodiment, the inherentviscosity is from 0.2-0.3 dl/g. In another embodiment, the inherentviscosity is from 0.25-0.35 dl/g. In another embodiment the inherentviscosity is from 0.3-0.4 dl/g. In another embodiment, the inherentviscosity is from 0.35-0.45 dl/g. In another embodiment, the inherentviscosity is from 0.4-0.5 dl/g. In another embodiment, the inherentviscosity is from 0.45-0.55 dl/g. In another embodiment, the inherentviscosity is from 0.5-0.6 dl/g. In another embodiment, the inherentviscosity is from 0.55-0.65 dl/g. In another embodiment the inherentviscosity is from 0.6-0.7 dl/g. In another embodiment, the inherentviscosity is from 0.65-0.75 dl/g. In another embodiment, the inherentviscosity is from 0.7-0.8 dl/g. In another embodiment, the inherentviscosity is from 0.75-0.85 dl/g. In another embodiment, the inherentviscosity is from 0.8-0.9 dl/g. In another embodiment, the inherentviscosity is from 0.85-0.95 dl/g. In another embodiment, the inherentviscosity is from 0.2-0.35 dl/g. In another embodiment, the inherentviscosity is from 0.25-0.40 dl/g. In another embodiment, the inherentviscosity is from 0.3-0.45 dl/g. In another embodiment, the inherentviscosity is from 0.35-0.5 dl/g. In another embodiment, the inherentviscosity is from 0.4-0.55 dl/g. In another embodiment, the inherentviscosity is from 0.45-0.6 dl/g. In another embodiment, the inherentviscosity is from 0.5-0.65 dl/g. In another embodiment, the inherentviscosity is from 0.55-0.70 dl/g. In another embodiment, the inherentviscosity is from 0.6-0.75 dl/g. In another embodiment, the inherentviscosity is from 0.65-0.80 dl/g. In another embodiment, the inherentviscosity is from 0.7-0.85 dl/g. In another embodiment, the inherentviscosity is from 0.75-0.9 dl/g. In another embodiment, the inherentviscosity is from 0.8-0.95 dl/g. In another embodiment, the inherentviscosity is from 0.2-0.40 dl/g. In another embodiment, the inherentviscosity is from 0.25-0.45 dl/g. In another embodiment, the inherentviscosity is from 0.3-0.5 dl/g. In another embodiment, the inherentviscosity is from 0.35-0.55 dl/g. In another embodiment, the inherentviscosity is from 0.4-0.6 dl/g. In another embodiment, the inherentviscosity is from 0.45-0.65 dl/g. In another embodiment, the inherentviscosity is from 0.5-0.7 dl/g. In another embodiment, the inherentviscosity is from 0.55-0.75 dl/g. In another embodiment, the inherentviscosity is from 0.6-0.8 dl/g. In another embodiment, the inherentviscosity is from 0.65-0.85 dl/g. In another embodiment, the inherentviscosity is from 0.7-0.9 dl/g. In another embodiment, the inherentviscosity is from 0.75-0.95 dl/g. In another embodiment, the inherentviscosity is from 0.2-0.45 dl/g. In another embodiment, the inherentviscosity is from 0.25-0.5 dl/g. In another embodiment, the inherentviscosity is from 0.3-0.55 dl/g. In another embodiment, the inherentviscosity is from 0.35-0.6 dl/g. In another embodiment, the inherentviscosity is from 0.4-0.65 dl/g. In another embodiment, the inherentviscosity is from 0.45-0.7 dl/g. In another embodiment, the inherentviscosity is from 0.5-0.75 dl/g. In another embodiment, the inherentviscosity is from 0.55-0.80 dl/g. In another embodiment, the inherentviscosity is from 0.6-0.85 dl/g. In another embodiment, the inherentviscosity is from 0.65-0.9 dl/g. In another embodiment, the inherentviscosity is from 0.7-0.95 dl/g.

In another embodiment, the inherent viscosity is 0.2 dl/g. In anotherembodiment, the inherent viscosity is 0.25 dl/g. In another embodiment,the inherent viscosity is 0.3 dl/g. In another embodiment, the inherentviscosity is 0.35 dl/g. In another embodiment, the inherent viscosity is0.4 dl/g. In another embodiment, the inherent viscosity is 0.45 dl/g. Inanother embodiment, the inherent viscosity is 0.5 dl/g. In anotherembodiment, the inherent viscosity is 0.55 dl/g. In another embodiment,the inherent viscosity is 0.6 dl/g. In another embodiment, the inherentviscosity is 0.65 dl/g. In another embodiment, the inherent viscosity is0.7 dl/g. In another embodiment, the inherent viscosity is 0.75 dl/g. Inanother embodiment, the inherent viscosity is 0.8 dl/g. In anotherembodiment, the inherent viscosity is 0.85 dl/g. In another embodiment,the inherent viscosity is 0.9 dl/g. In another embodiment, the inherentviscosity is 0.95 dl/g.

Each of the above inherent viscosities represents a separate embodimentof the present invention.

“Inherent viscosity” refers, in one embodiment, to a measure of thecapability of a polymer in solution to enhance the viscosity of thesolution. In another embodiment, intrinsic viscosity increases withincreasing polymer molecular weight, is a function of polymerizationconditions, and may be varied independently of the PLA:PGA ratio of thepolymer. In another embodiment, intrinsic viscosity is defined as thelimiting value of the specific viscosity/concentration ratio at zeroconcentration. Thus, viscosity is determined at different concentrationsand then is extrapolated to zero concentration. In another embodiment,“inherent viscosity” is a synonym for “intrinsic viscosity.” Eachdefinition for “inherent viscosity” represents a separate embodiment ofthe present invention.

Methods for measuring inherent viscosity are well known in the art, andare described, for example, in Meek M F et al (J Biomed Mater Res A68(1): 43-51, 2004) and Deng X et al (J Control Release 71(2):165-73,2001). In another embodiment, inherent viscosity is measured asdescribed in Example 1 of the present disclosure. In another embodiment,inherent viscosity is measured in chloroform. In another embodiment,inherent viscosity is measured in hexafluoroisopropanol solution. Inanother embodiment, inherent viscosity is measured in any other suitablesolvent known in the art. In another embodiment, the solvent is an FDAClass III solvent (low toxicity with minimal need for removal ofresidual solvent). Each method represents a separate embodiment of thepresent invention.

In another embodiment, an implant of methods and compositions of thepresent invention has a surface area to volume (SA:V) ratio betweenabout 1 and 3 (millimeters [mm])²/mm³. In another embodiment, the ratiois between 0.5-1 mm²/mm³. In another embodiment, the ratio is from0.7-1.2 mm²/mm³. In another embodiment, the ratio is from 0.9-1.4mm²/mm³. In another embodiment, the ratio is from 1.1-1.6 mm²/mm³. Inanother embodiment, the ratio is from 1.3-1.8 mm²/mm³. In anotherembodiment, the ratio is from 1.5-2 mm²/mm³. In another embodiment, theratio is from 2-2.5 mm²/mm³. In another embodiment, the ratio is from2.5-3 mm²/mm³. In another embodiment, the ratio is from 3-3.5 mm²/mm³.In another embodiment, the ratio is from 3.5-4 mm²/mm³. In anotherembodiment, the ratio is from 4-4.5 mm²/mm³. In another embodiment, theratio is from 4.5-5 mm²/mm³. In another embodiment, the ratio is from5-5.5 mm²/mm³. In another embodiment, the ratio is from 5.5-6 mm²/mm³.In another embodiment, the ratio is between 0.5-1.5 mm²/mm³. In anotherembodiment, the ratio is from 1-2 mm²/mm³. In another embodiment, theratio is from 1.5-2.5 mm²/mm³. In another embodiment, the ratio is from2-3 mm²/mm³. In another embodiment, the ratio is from 2.5-3.5 mm²/mm³.In another embodiment, the ratio is from 3-4 mm²/mm³. In anotherembodiment, the ratio is from 3.5-4.5 mm²/mm³. In another embodiment,the ratio is from 4-5 mm²/mm³. In another embodiment, the ratio is from4.5-5.5 mm²/mm³. In another embodiment, the ratio is from 5-6 mm²/mm³.In another embodiment, the ratio is from 5.5-6.5 mm²/mm³. In anotherembodiment, the ratio is from 6-7 mm²/mm³. In another embodiment, theratio is from 6.5-7.5 mm²/mm³. In another embodiment, the ratio is from7-8 mm²/mm³. In another embodiment, the ratio is between 0.5-2 mm²/mm³.In another embodiment, the ratio is from 1-2.5 mm²/mm³. In anotherembodiment, the ratio is from 1.5-3 mm²/mm³. In another embodiment, theratio is from 2-3.5 mm²/mm³. In another embodiment, the ratio is from2.5-4 mm²/mm³. In another embodiment, the ratio is from 3-4.5 mm²/mm³.In another embodiment, the ratio is from 3.5-5 mm²/mm³. In anotherembodiment, the ratio is from 4-5.5 mm²/mm³. In another embodiment, theratio is from 4.5-6 mm²/mm³. In another embodiment, the ratio is from5-6.5 mm²/mm³. In another embodiment, the ratio is from 5.5-7 mm²/mm³.In another embodiment, the ratio is from 6-7.5 mm²/mm³. In anotherembodiment, the ratio is from 6.5-8 mm²/mm³. In another embodiment, theratio is from 0.5-2.5 mm²/mm³. In another embodiment, the ratio is from1-3 mm²/mm³. In another embodiment, the ratio is from 1.5-3.5 mm²/mm³.In another embodiment, the ratio is from 2-4 mm²/mm³. In anotherembodiment, the ratio is from 2.5-4.5 mm²/mm³. In another embodiment,the ratio is from 3-5 mm²/mm³. In another embodiment, the ratio is from3.5-5.5 mm²/mm³. In another embodiment, the ratio is from 4-6 mm²/mm³.In another embodiment, the ratio is from 4.5-6.5 mm²/mm³. In anotherembodiment, the ratio is from 5-7 mm²/mm³. In another embodiment, theratio is from 5.5-7.5 mm²/mm³. In another embodiment, the ratio is from6-8 mm²/mm³. In another embodiment, the ratio is between 0.5-3.5mm²/mm³. In another embodiment, the ratio is from 1-4 mm²/mm³. Inanother embodiment, the ratio is from 1.5-4.5 mm²/mm³. In anotherembodiment, the ratio is from 2-5 mm²/mm³. In another embodiment, theratio is from 2.5-5.5 mm²/mm³. In another embodiment, the ratio is from3-6 mm²/mm³. In another embodiment, the ratio is from 3.5-6.5 mm²/mm³.In another embodiment, the ratio is from 4-7 mm²/mm³. In anotherembodiment, the ratio is from 4.5-7.5 mm²/mm³. In another embodiment,the ratio is from 6-8 mm²/mm³. In another embodiment, the ratio isbetween 0.5-4.5 mm²/mm³. In another embodiment, the ratio is from 1-5mm²/mm³. In another embodiment, the ratio is from 1.5-5.5 mm²/mm³. Inanother embodiment, the ratio is from 2-6 mm²/mm³. In anotherembodiment, the ratio is from 2.5-6.5 mm²/mm³. In another embodiment,the ratio is from 3-7 mm²/mm³. In another embodiment, the ratio is from3.5-7.5 mm²/mm³. In another embodiment, the ratio is from 4-8 mm²/mm³.In another embodiment, the ratio is from 4.5-8.5 mm²/mm³.

In another embodiment, the ratio is 0.5 mm²/mm³. In another embodiment,the ratio is 0.6 mm²/mm³. In another embodiment, the ratio is 0.7mm²/mm³. In another embodiment, the ratio is 0.8 mm²/mm³. In anotherembodiment, the ratio is 1.0 mm²/mm³. In another embodiment, the ratiois 1.5 mm²/mm³. In another embodiment, the ratio is 2 mm²/mm³. Inanother embodiment, the ratio is 2.5 mm²/mm³. In another embodiment, theratio is 3 mm²/mm³. In another embodiment, the ratio is 3.5 mm²/mm³. Inanother embodiment, the ratio is 4 mm²/mm³. In another embodiment, theratio is 4.5 mm²/mm³. In another embodiment, the ratio is 5 mm²/mm³. Inanother embodiment, the ratio is 5.5 mm²/mm³. In another embodiment, theratio is 6 mm²/mm³. In another embodiment, the ratio is 6.5 mm²/mm³. Inanother embodiment, the ratio is 7 mm²/mm³. Each of the above SA:Vratios represents a separate embodiment of the present invention.

As provided herein (Example 6), results of the present invention havedemonstrated the efficacy of particular SA:V ratio ranges ofbiodegradable implants. Methods for measuring SA:V ratio are well knownin the art. SA:V ratio is measured, in one embodiment, by calculatingthe surface area and volume from the measurements of the shape (e.g. fora regular shape). In another embodiment (e.g. for an irregular shape),surface area is measured using a BET (Brunauer, Emmett and Teller)apparatus (J de Kanel and J W Morse, J Phys E: Sci Instrum 12: 272-273,1979). In another embodiment, surface area is measured using any othertechnique known in the art. In another embodiment, volume is measured bydisplacement of water or another fluid. In another embodiment, volume ismeasured using any other technique known in the art. Each possibilityrepresents a separate embodiment of the present invention.

In another embodiment, an implant of methods and compositions of thepresent invention has a length between about 1-5 mm. “Length,” in oneembodiment, refers to the longest dimension of the implant. In anotherembodiment, “length” refers to the length of the straight-edgedimension—e.g. in the case of a cylindrical-shaped implant. In anotherembodiment, the “straight-edge dimension” referred to need not becompletely straight, but can be, e.g. a slight curve. Each possibilityrepresents a separate embodiment of the present invention.

In another embodiment, the length of the implant is between 1-2 mm. Inanother embodiment, the length is from 0.5-1.0 mm. In anotherembodiment,the length is from 1.5-2 mm. In another embodiment, thelength is from 2-2.5 mm. In another embodiment, the length is from 2.5-3mm. In another embodiment, the length is from 3-3.5 mm. In anotherembodiment, the length is from 3.5-4 mm. In another embodiment, thelength is from 4-4.5 mm. In another embodiment, the length is from 4.5-5mm. In another embodiment, the length is from 5-5.5 mm. In anotherembodiment, the length is from 0.5-1.5 mm. In another embodiment, thelength is from 1.5-2.5 mm. In another embodiment, the length is from 2-3mm. In another embodiment, the length is from 2.5-3.5 mm. In anotherembodiment, the length is from 3-4 mm. In another embodiment, the lengthis from 3.5-4.5 mm. In another embodiment, the length is from 4-5 mm. Inanother embodiment, the length is from 4.5-5.5 mm. In anotherembodiment, the length is from 5-6 mm. In another embodiment, the lengthis from 0.5-2 mm. In another embodiment, the length is from 1-2.5 mm. Inanother embodiment, the length is from 1.5-3 mm. In another embodiment,the length is from 2-3.5 mm. In another embodiment, the length is from2.5-4 mm. In another embodiment, the length is from 3-4.5 mm. In anotherembodiment, the length is from 3.5-5 mm. In another embodiment, thelength is from 4-5.5 mm. In another embodiment, the length is from 4.5-6mm. In another embodiment, the length is from 0.5-2.5 mm. In anotherembodiment, the length is from 1-3 mm. In another embodiment, the lengthis from 1.5-3.5 mm. In another embodiment, the length is from 2-4 mm. Inanother embodiment, the length is from 2.5-4.5 mm. In anotherembodiment, the length is from 3-5 mm. In another embodiment, the lengthis from 3.5-5.5 mm. In another embodiment, the length is from 4-6 mm. Inanother embodiment, the length is from 4.5-6.5 mm. In anotherembodiment, the length is from 5-7 mm. In another embodiment, the lengthis from 0.5-3.5 mm. In another embodiment, the length is from 1-4 mm. Inanother embodiment, the length is from 2-5 mm. In another embodiment,the length is from 3-6 mm. In another embodiment, the length is from 4-7mm. In another embodiment, the length is from 5-8 mm. In anotherembodiment, the length is from 0.5-4.5 mm. In another embodiment, thelength is from 1-5 mm. In another embodiment, the length is from 2-6 mm.In another embodiment, the length is from 3-7 mm.

In another embodiment, the length is 0.5 mm. In another embodiment, thelength is 0.6 mm. In another embodiment, the length is 0.7 mm. Inanother embodiment, the length is 0.8 mm. In another embodiment, thelength is 0.9 mm. In another embodiment, the length is 1.0 mm. Inanother embodiment, the length is 1.2 mm. In another embodiment, thelength is 1.4 mm. In another embodiment, the length is 1.6 mm. Inanother embodiment, the length is 1.8 mm. In another embodiment, thelength is 2.0 mm. In another embodiment, the length is 2.2 mm. Inanother embodiment, the length is 2.4 mm. In another embodiment, thelength is 2.6 mm. In another embodiment, the length is 2.8 mm. Inanother embodiment, the length is 3.0 mm. In another embodiment, thelength is 3.5 mm. In another embodiment, the length is 4 mm. In anotherembodiment, the length is 4.5 mm. In another embodiment, the length is 5mm. In another embodiment, the length is 5.5 mm. In another embodiment,the length is 6 mm. In another embodiment, the length is 7 mm. Inanother embodiment, the length is 8 mm. Each of the above lengthsrepresents a separate embodiment of the present invention.

In another embodiment, an implant of methods and compositions of thepresent invention has a diameter between about 24 mm. “Diameter,” in oneembodiment, refers to the distance across the cross-sectional area ofthe implant. In another embodiment, e.g. in the case of a disk-shapedimplant, the distance across the cross-sectional area may be longer thanthe length described above. In another embodiment, e.g. in the case of arod-shaped implant, the distance across the cross-sectional area isshorter than the length. In another embodiment, the cross-sectional areareferred to need not be a circle, but may be an ellipse, square,rectangle, etc. as described above. Thus, in another embodiment, thediameter is the geometric mean of the longest and shortest diameters ofthe cross-sectional area. In another embodiment, the diameter is thearithmetic mean of the longest and shortest diameters thereof. Inanother embodiment, the diameter is the longest of the various diametersthereof. In another embodiment, the diameter is the distance across adiagonal of the cross-sectional area—e.g. in the case of a square orrectangle. In another embodiment, the diameter is the distance acrossthe largest cross-sectional area—e.g. in a case in which the diametervaries over the length of implant. In another embodiment, the diameteris the average distance across the largest cross-sectional area. Eachpossibility represents a separate embodiment of the present invention.

In another embodiment, the diameter is between about 2-4 mm. In anotherembodiment, the diameter is from 0.5-1 mm. In another embodiment, thediameter is from 1-1.5 mm. In another embodiment, the diameter is from1.5-2 mm. In another embodiment, the diameter is from 2-2.5 mm. Inanother embodiment, the diameter is from 2.5-3 mm. In anotherembodiment, the diameter is from 3-3.5 mm. In another embodiment, thediameter is from 3.5-4 mm. In another embodiment, the diameter is from4-4.5 mm. In another embodiment, the diameter is from 4.5-5 mm. Inanother embodiment, the diameter is from 5-5.5 mm. In anotherembodiment, the diameter is from 5.5-6 mm. In another embodiment, thediameter is from 0.5-1.5 mm. In another embodiment, the diameter is from1-2 mm. In another embodiment, the diameter is from 1.5-2.5 mm. Inanother embodiment, the diameter is from 2-3 mm. In another embodiment,the diameter is from 2.5-3.5 mm. In another embodiment, the diameter isfrom 3-4 mm. In another embodiment, the diameter is from 3.5-4.5 mm. Inanother embodiment, the diameter is from 4-5 mm. In another embodiment,the diameter is from 4.5-5.5 mm. In another embodiment, the diameter isfrom 5-6 mm. In another embodiment, the diameter is from 0.5-2 mm. Inanother embodiment, the diameter is from 1-2.5 mm. In anotherembodiment, the diameter is from 1.5-3 mm. In another embodiment, thediameter is from 2-3.5 mm. In another embodiment, the diameter is from2.5-4 mm. In another embodiment, the diameter is from 3-4.5 mm. Inanother embodiment, the diameter is from 3.5-5 mm. In anotherembodiment, the diameter is from 4-5.5 mm. In another embodiment, thediameter is from 4.5-6 mm. In another embodiment, the diameter is from1-3 mm. In another embodiment, the diameter is from 1.5-3.5 mm. Inanother embodiment, the diameter is from 2-4 mm. In another embodiment,the diameter is from 2.5-4.5 mm. In another embodiment, the diameter isfrom 3-5 mm. In another embodiment, the diameter is from 3.5-5.5 mm. Inanother embodiment, the diameter is from 4-6 mm. In another embodiment,the diameter is from 1-4 mm. In another embodiment, the diameter is from2-5 mm. In another embodiment, the diameter is from 3-6 mm. In anotherembodiment, the diameter is from 4-7 mm.

In another embodiment, the diameter is 0.5 mm. In another embodiment,the diameter is 0.6 mm. In another embodiment, the diameter is 0.7 mm.In another embodiment, the diameter is 0.8 mm. In another embodiment,the diameter is 0.9 mm. In another embodiment, the diameter is 1.0 mm.In another embodiment, the diameter is 1.2 mm. In another embodiment,the diameter is 1.4 mm. In another embodiment, the diameter is 1.6 mm.In another embodiment, the diameter is 1.8 mm. In another embodiment,the diameter is 2.0 mm. In another embodiment, the diameter is 2.2 mm.In another embodiment, the diameter is 2.4 mm. In another embodiment,the diameter is 2.6 mm. In another embodiment, the diameter is 2.8 mm.In another embodiment, the diameter is 3.0 mm. In another embodiment,the diameter is 3.2 mm. In another embodiment, the diameter is 3.4 mm.In another embodiment, the diameter is 3.6 mm. In another embodiment,the diameter is 3.8 mm. In another embodiment, the diameter is 4.0 mm.In another embodiment, the diameter is 4.2 mm. In another embodiment,the diameter is 5 mm. In another embodiment, the diameter is 5.5 mm. Inanother embodiment, the diameter is 6 mm. Each of the above diametersrepresents a separate embodiment of the present invention.

In another embodiment, an implant of methods and compositions of thepresent invention has a mass of about 0.75 grams (g) or less. Asprovided herein, the present invention demonstrates the feasibility ofutilizing an implant of about 0.75 g or less for delivery of 6 months'effective dose of risperidone for a human (Example 14). In anotherembodiment, the present invention demonstrates the feasibility ofutilizing an implant of about 1.5 g or less for delivery of one year'seffective dose of risperidone. In another embodiment, the implant has amass of about 0.1 g or less. In another embodiment, the mass is 0.2 g orless. In another embodiment, the mass is 0.3 g or less. In anotherembodiment, the mass is 0.4 g or less. In another embodiment, the massis 0.5 g or less. In another embodiment, the mass is 0.6 g or less. Inanother embodiment, the mass is 0.7 g or less. In another embodiment,the mass is 0.8 g or less. In another embodiment, the mass is 0.9 g orless. In another embodiment, the mass is 1 g or less. In anotherembodiment, the mass is 1.1 g or less. In another embodiment, the massis 1.2 g or less. In another embodiment, the mass is 1.3 g or less. Inanother embodiment, the mass is 1.4 g or less. In another embodiment,the mass is 1.5 g or less. In another embodiment, the mass is 1.6 g orless. In another embodiment, the mass is 1.7 g or less. In anotherembodiment, the mass is 1.8 g or less. In another embodiment, the massis 1.9 g or less. In another embodiment, the mass is 2 g or less. Inanother embodiment, the mass is 2.2 g or less. In another embodiment,the mass is 2.4 g or less. In another embodiment, the mass is 2.6 g orless. In another embodiment, the mass is 2.8 g or less. In anotherembodiment, the mass is 3 g or less.

In another embodiment, the mass is 0.1 g. In another embodiment, themass is 0.2 g. In another embodiment, the mass is 0.3 g. In anotherembodiment, the mass is 0.4 g. In another embodiment, the mass is 0.5 g.In another embodiment, the mass is 0.6 g. In another embodiment, themass is 0.7 g. In another embodiment, the mass is 0.8 g. In anotherembodiment, the mass is 0.9 g. In another embodiment, the mass is 1 g.In another embodiment, the mass is 1.1 g. In another embodiment, themass is 1.2 g. In another embodiment, the mass is 1.3 g. In anotherembodiment, the mass is 1.4 g. In another embodiment, the mass is 1.5 g.In another embodiment, the mass is 1.6 g. In another embodiment, themass is 1.7 g. In another embodiment, the mass is 1.8 g. In anotherembodiment, the mass is 1.9 g. In another embodiment, the mass is 2 g.In another embodiment, the mass is 2.2 g. In another embodiment, themass is 2.4 g. In another embodiment, the mass is 2.6 g. In anotherembodiment, the mass is 2.8 g. In another embodiment, the mass is 3 g.

In another embodiment, the mass is between about 0.1-0.3 g. In anotherembodiment, the mass is from 0.2-0.4 g. In another embodiment, the massis from 0.3-0.5 g. In another embodiment, the mass is from 0.4-0.6 g. Inanother embodiment, the mass is from 0.5-0.7 g. In another embodiment,the mass is from 0.6-0.8 g. In another embodiment, the mass is from0.7-0.9 g. In another embodiment, the mass is from 0.8-1.0 g. In anotherembodiment, the mass is from 0.1-0.4 g. In another embodiment, the massis from 0.2-0.5 g. In another embodiment, the mass is from 0.3-0.6 g. Inanother embodiment, the mass is from 0.4-0.7 g. In another embodiment,the mass is from 0.5-0.8 g. In another embodiment, the mass is from0.6-0.9 g. In another embodiment, the mass is from 0.7-1.0 g. In anotherembodiment, the mass is from 0.1-0.5 g. In another embodiment, the massis from 0.2-0.6 g. In another embodiment, the mass is from 0.3-0.7 g. Inanother embodiment, the mass is from 0.4-0.8 g. In another embodiment,the mass is from 0.5-0.9 g. In another embodiment, the mass is from0.6-1.0 g. In another embodiment, the mass is from 0.8-1.2 g. In anotherembodiment, the mass is from 1.0-1.4 g. In another embodiment, the massis from 1.2-1.6 g. In another embodiment, the mass is from 1.4-1.8 g. Inanother embodiment, the mass is from 1.6-2 g. In another embodiment, themass is from 1.8-2.2 g. In another embodiment, the mass is from 2-2.4 g.In another embodiment, the mass is from 2.5-2.9 g. In anotherembodiment, the mass is from 0.1-0.6 g. In another embodiment, the massis from 0.2-0.7 g. In another embodiment, the mass is from 0.3-0.8 g. Inanother embodiment, the mass is from 0.4-0.9 g. In another embodiment,the mass is from 0.5-1.0 g. In another embodiment, the mass is from0.6-1.1 g. In another embodiment, the mass is from 0.8-1.3 g. In anotherembodiment, the mass is from 1.0-1.5 g. In another embodiment, the massis from 1.2-1.7 g. In another embodiment, the mass is from 1.4-1.9 g. Inanother embodiment, the mass is from 1.6-2.1 g. In another embodiment,the mass is from 1.8-2.3 g. In another embodiment, the mass is from2-2.5 g. In another embodiment, the mass is from 2.5-3 g. In anotherembodiment, the mass is from 0.1-0.8 g. In another embodiment, the massis from 0.2-0.9 g. In another embodiment, the mass is from 0.3-1.1 g. Inanother embodiment, the mass is from 0.5-1.2 g. In another embodiment,the mass is from 0.6-1.3 g. In another embodiment, the mass is from0.8-1.5 g. In another embodiment, the mass is from 1.0-1.7 g. In anotherembodiment, the mass is from 1.2-1.9 g. In another embodiment, the massis from 1.6-2.1 g. In another embodiment, the mass is from 1.8-2.5 g. Inanother embodiment, the mass is from 2-2.7 g. In another embodiment, themass is from 0.1-1.1 g. In another embodiment, the mass is from 0.2-1.2g. In another embodiment, the mass is from 0.3-1.3 g. In anotherembodiment, the mass is from 0.5-1.5 g. In another embodiment, the massis from 0.6-1.6 g. In another embodiment, the mass is from 0.8-1.8 g. Inanother embodiment, the mass is from 1.0-2 g. In another embodiment, themass is from 1.5-2.5 g. In another embodiment, the mass is from 2-3 g.In another embodiment, the mass is from 0.2-1.7 g. In anotherembodiment, the mass is from 0.3-1.8 g. In another embodiment, the massis from 0.5-2 g. In another embodiment, the mass is from 0.8-2.3 g. Inanother embodiment, the mass is from 1.0-2.5 g. In another embodiment,the mass is from 1.5-3 g. In another embodiment, the mass is from0.2-2.2 g. In another embodiment, the mass is from 0.3-2.3 g. In anotherembodiment, the mass is from 0.5-2.5 g. In another embodiment, the massis from 0.8-2.8 g. In another embodiment, the mass is from 1-3 g.

Each of the above masses represents a separate embodiment of the presentinvention.

In another embodiment, an implant of methods and compositions of thepresent invention is manufactured by solvent casting. In anotherembodiment, the implant is manufactured by compression molding. Inanother embodiment, the implant is manufactured by extrusion molding. Inone embodiment, the extrusion molding is high-pressure extrusionmolding. In one embodiment, implants manufactured by compression moldingexhibit increased density. In another embodiment, implants manufacturedby compression molding exhibit improved uniformity. In anotherembodiment, a greater variety of shapes of implants can be manufacturedby compression molding. In another embodiment, less material is lostduring fabrication in the case of implants manufactured by extruding.Each possibility represents a separate embodiment of the presentinvention.

In another embodiment, the invention provides a method for treating asubject for a disorder associated with a likelihood of non-compliance.The method includes administering to a subject a target therapeutic drugin a long-term delivery system comprising an implantable, rod shapedstructure and the target therapeutic drug.

In another embodiment, the present invention provides a method formaintaining a therapeutic level of a drug in a subject for a period ofat least about 4 months, comprising administering to the subject a setof biodegradable implants, the set of biodegradable implants consistingof one or more individual biodegradable implants having (a) atherapeutic drug present in an amount of 10%-60% by mass, relative tothe mass of the implant; and (b) a polymer present in an amount of40%-70% by mass, relative to the mass of the implant, the polymercomprising PLA and optionally PGA in a PLA:PGA molar ratio between 50:50and 100:0 and wherein the individual biodegradable implants, if morethan one in number, do not differ substantially from one another intheir PLA:PGA molar ratio, thereby maintaining a therapeutic level of adrug in a subject for a period of at least about 4 months.

In another embodiment, the individual implants are equivalent to oneanother in another parameter in addition to their PLA:PGA molar ratio,e.g. their drug load, mass, SA:V ratio, length, diameter, or inherentviscosity of the polymer. In another embodiment, the individual implantsare equivalent to one another in their PLA:PGA ratio, but not in theother parameters. In another embodiment, the individual implants areequivalent to one another in two of these other parameters in additionto their PLA:PGA ratio. In another embodiment, the individual implantsare equivalent to one another in three of these other parameters inaddition to their PLA:PGA ratio. In another embodiment, the individualimplants are equivalent to one another in four of these other parametersin addition to their PLA:PGA ratio. In another embodiment, theindividual implants are equivalent to one another in five of these otherparameters in addition to their PLA:PGA ratio. In another embodiment,the individual implants are equivalent to one another in all of theseother parameters in addition to their PLA:PGA ratio. Each possibilityrepresents a separate embodiment of the present invention.

In another embodiment, the individual implants are equivalent to oneanother in their drug load instead of in their PLA:PGA ratio. In anotherembodiment, the individual implants are equivalent to one another intheir mass instead of in their PLA:PGA ratio. In another embodiment, theindividual implants are equivalent to one another in their SA:V ratioinstead of in their PLA:PGA ratio. In another embodiment, the individualimplants are equivalent to one another in their length instead of intheir PLA:PGA ratio. In another embodiment, the individual implants areequivalent to one another in their diameter instead of in their PLA:PGAratio. In another embodiment, the individual implants are equivalent toone another in the inherent viscosity of their polymer instead of intheir PLA:PGA ratio. In another embodiment, the individual implants areequivalent to one another in 2 of these parameters. In anotherembodiment, the individual implants are equivalent to one another in 3of these parameters. In another embodiment, the individual implants areequivalent to one another in 4 of these parameters. In anotherembodiment, the individual implants are equivalent to one another in allof these parameters. Each possibility represents a separate embodimentof the present invention.

In another embodiment, the PLA:PGA ratio is substantially invariantwithin the individual implants; e.g. the individual implants are noteach composed of sections with different PLA:PGA ratios. In anotherembodiment, this is true of the drug load of the individual implants. Inanother embodiment, this is true of the mass of the individual implants.In another embodiment, this is true of the SA:V ratio of the individualimplants. In another embodiment, this is true of the length of theindividual implants. In another embodiment, this is true of the diameterof the individual implants. In another embodiment, this is true of theinherent viscosity of the polymer in the individual implants. Eachpossibility represents a separate embodiment of the present invention.

As provided herein, the present invention demonstrates that extendedmaintenance of therapeutic drug levels can be attained with asingle-polymer system (e.g. a homogenous set of implants). Furthermore,the single-polymer implant system in rabbits (FIG. 3B) demonstrated thatindividual polymers approximate a symmetrical pattern of serumconcentration. Moreover, as depicted in FIG. 3B, the trendline thatdescribed that data with a correlation coefficient (R2) of 0.86exhibited maximum release values at approximately 6 months.

In another embodiment, the present invention provides a method formaintaining a therapeutic level of a drug in a subject for a period ofat least about one year, comprising (1) administering to the subject aninitial set of one or more biodegradable implants, wherein the initialset consists of one or more individual biodegradable implants having (a)a therapeutic drug present in an amount of 10%-60% by mass, relative tothe mass of the implant; and (b) a polymer present in an amount of40%-70% by mass, relative to the mass of the implant, the polymercomprising PLA and optionally PGA in a PLA:PGA molar ratio between 50:50and 100:0; and (2) administering to the subject a maintenance set of oneor more biodegradable implants to the subject near the point of peakrelease of the initial set of biodegradable implants, wherein themaintenance set of biodegradable implants consists of additionalindividual biodegradable implants equivalent in the PLA:PGA molar ratioto the individual biodegradable implants in the initial set ofbiodegradable implants. In this method, the individual biodegradableimplants of the initial set, if more than one in number, do not differsubstantially from one another in their PLA:PGA molar ratio, therebymaintaining a therapeutic level of a drug in a subject for a period ofat least about one year.

In another embodiment, the present invention provides a method formaintaining a therapeutic level of a drug in a subject for a period ofat least about 6 months, comprising (1) administering to the subject aninitial set of one or more biodegradable implants, wherein the initialset consists of one or more individual biodegradable implants having (a)a therapeutic drug present in an amount of 10%-60% by mass, relative tothe mass of the implant; and (b) a polymer present in an amount of40%-70% by mass, relative to the mass of the implant, the polymercomprising PLA and optionally PGA in a PLA:PGA molar ratio between 50:50and 100:0; and (2) administering to the subject a maintenance set of oneor more biodegradable implants to the subject near the point of peakrelease of the initial set of biodegradable implants, wherein themaintenance set of biodegradable implants consists of additionalindividual biodegradable implants equivalent in the PLA:PGA molar ratioto the individual biodegradable implants in the initial set ofbiodegradable implants. In this method, the individual biodegradableimplants of the initial set, if more than one in number, do not differsubstantially from one another in their PLA:PGA molar ratio, therebymaintaining a therapeutic level of a drug in a subject for a period ofat least about 6 months.

In another embodiment, the individual biodegradable implants of themaintenance set, if more than one in number, do not differ substantiallyfrom one another in their PLA:PGA molar ratio. In another embodiment,the individual biodegradable implants of the initial set and themaintenance set do not differ substantially from one another, bothwithin and between the sets, in their PLA:PGA molar ratio. Eachpossibility represents a separate embodiment of the present invention.

In another embodiment, step (b) is repeated as necessary to maintaintherapeutic level of the drug for the desired time period in thesubject.

In another embodiment, the maintenance set is administered near the timeof beginning of decline of drug release of the prior set of implants.

In one embodiment, the maintenance set is administered about once every6 month. In another embodiment, the maintenance set is administeredafter a period of about 5 months. In another embodiment, the period isabout 4 months In another embodiment, the period is about 3 months. Inanother embodiment, the period is about 2 months. In another embodiment,the period is about 6 weeks. In another embodiment, the period is about1 month. In another embodiment, the period is about 7 months. In anotherembodiment, the period is about 8 months. In another embodiment, theperiod is about 9 months. In another embodiment, the period is about 10months. In another embodiment, the period is about 11 months. In anotherembodiment, the period is about 12 months. In another embodiment, theperiod is about 14 months. In another embodiment, the period is about 16months. In another embodiment, the period is about 18 months. In anotherembodiment, the period is about 20 months. In another embodiment, theperiod is about 22 months. In another embodiment, the period is about 24months. In another embodiment, the period is about 30 months. In anotherembodiment, the period is about 36 months. Each possibility represents aseparate embodiment of the present invention.

In another embodiment, the individual implants of the maintenance setare equivalent to the individual implants in the initial set in anotherparameter in addition to their PLA:PGA molar ratio, e.g. their drugload, mass, SA:V ratio, length, diameter, or inherent viscosity of thepolymer. In another embodiment, the individual implants of themaintenance set are equivalent to the individual implants in the initialset in one of these parameters instead of their PLA:PGA molar ratio. Inanother embodiment, the individual implants from the maintenance set areequivalent to the individual implants in the initial set in theirPLA:PGA ratio, but not in the other parameters. In another embodiment,the individual implants from the maintenance set are equivalent to theindividual implants in the initial set in two of these other parametersin addition to their PLA:PGA ratio. In another embodiment, theindividual implants from the maintenance set are equivalent to theindividual implants in the initial set in three of these otherparameters in addition to their PLA:PGA ratio. In another embodiment,the individual implants from the maintenance set are equivalent to theindividual implants in the initial set in four of these other parametersin addition to their PLA:PGA ratio. In another embodiment, theindividual implants from the maintenance set are equivalent to theindividual implants in the initial set in five of these other parametersin addition to their PLA:PGA ratio. In another embodiment, theindividual implants from the maintenance set are equivalent to theindividual implants in the initial set in all of these other parametersin addition to their PLA:PGA ratio. In another embodiment, theindividual implants from the maintenance set are equivalent to theindividual implants in the initial set in two of these other parameters,but not their PLA:PGA ratio. In another embodiment, the individualimplants from the maintenance set are equivalent to the individualimplants in the initial set in three of these other parameters, but nottheir PLA:PGA ratio. In another embodiment, the individual implants fromthe maintenance set are equivalent to the individual implants in theinitial set in four of these other parameters, but not their PLA:PGAratio. In another embodiment, the individual implants from themaintenance set are equivalent to the individual implants in the initialset in five of these other parameters, but not their PLA:PGA ratio. Eachpossibility represents a separate embodiment of the present invention.

In other embodiments, the individual implants of the maintenance sethave any of the characteristics described above for the individualimplants of the initial set. Each characteristic represents a separateembodiment of the present invention.

The nearly symmetrical nature of the release profile from single-polymersets, as demonstrated in the present invention, provides the possibilityof using overlapping implantations approximately every 6 months tosustain drug delivery indefinitely (FIG. 13). In one embodiment thisapproach offsets the steady decline from one set of implants with thegradual onset from a subsequent set.

In another embodiment, the time period over which the therapeutic levelof a drug is maintained by methods of the present invention is onemonth. In another embodiment, the period is 1.5 months. In anotherembodiment, the period is 2 months. In another embodiment, the period is2.5 months. In another embodiment, the period is 3 months. In anotherembodiment, the period is 3.5 months. In another embodiment, the periodis 4 months. In another embodiment, the period is 5 months. In anotherembodiment, the period is 6 months. In another embodiment, the period is7 months. In another embodiment, the period is 8 months. In anotherembodiment, the period is 9 months. In another embodiment, the period is10 months. In another embodiment, the period is 11 months. In anotherembodiment, the period is 12 months. In another embodiment, the periodis 13 months. In another embodiment, the period is 14 months. In anotherembodiment, the period is 15 months. In another embodiment, the periodis 16 months. In another embodiment, the period is 17 months. In anotherembodiment, the period is 18 months.

In another embodiment, the period begins 1 month after the step ofadministering the initial set of biodegradable implants. In anotherembodiment, the period begins 1 week after the initial administration.In another embodiment, the period begins 2 weeks after the initialadministration. In another embodiment, the period begins 3 weeks afterthe initial administration. In another embodiment, the period begins 5weeks after the initial administration. In another embodiment, theperiod begins 6 weeks after the initial administration. In anotherembodiment, the period begins 2 months after the initial administration.In another embodiment, the period begins 2.5 months after the initialadministration. In another embodiment, the period begins 3 months afterthe initial administration.

Each of the above periods represents a separate embodiment of thepresent invention.

In another embodiment, a method of the present invention furthercomprises administering to the subject a starter set of one or moredifferent biodegradable implants, wherein the implants of the starterset differ from the implants of the original set of implants in PLA:PGAratio, and whereby the implants of the starter set reach steady-statelevels of drug release faster than the initial set of implants. Inanother embodiment, the implants of the starter set differ from theimplants of the original set of implants in their drug load. In anotherembodiment, the starter set implants differ from original set ofimplants in their SA:V ratio. In another embodiment, the starter setimplants differ from the original set of implants in their mass. Inanother embodiment, the starter set implants differ from the originalset of implants in their length. In another embodiment, the starter setimplants differ from the original set of implants in their diameter. Inanother embodiment, the starter set implants differ from the originalset of implants in the inherent viscosity of their polymer. In anotherembodiment, the implants of the starter set differ from the original setof implants in 2 of these characteristics. In another embodiment, thestarter set implants differ from the original set of implants in 3 ofthese characteristics. In another embodiment, the starter set implantsdiffer from the original set of implants in 4 of these characteristics.In another embodiment, the starter set implants differ from the originalset of implants in all of these characteristics. Each possibilityrepresents a separate embodiment of the present invention.

In another embodiment, the implants of the starter set do not differsubstantially from one another in their PLA:PGA ratio, drug load,length, diameter, SA:V ratio, and inherent viscosity. In anotherembodiment, the starter set implants differ substantially from oneanother in one of these parameters. In another embodiment, the starterset implants differ substantially from one another in more than one ofthese parameters. In another embodiment, the starter set implants havedifferent release profiles from one another. Each possibility representsa separate embodiment of the present invention.

In other embodiments, the starter set implants have any of thecharacteristics described above for the individual implants of theinitial set. Each char acteristic represents a separate embodiment ofthe present invention.

In another embodiment, in methods of the present invention that comprisean initial set of implants and a maintenance set of equivalent implants,the starter set implants are administered together with the initial setof implants. “Together with,” in one embodiment, refers toadministration on the same day as the other set of one or more implants.In another embodiment, “together with” refers to administration during asingle operation or procedure. In another embodiment, the term refers toadministration within one day of the other set of implants. In anotherembodiment, the term refers to administration within 2 days of the otherset of implants. In another embodiment, the term refers toadministration within 3 days of the other set of implants. In anotherembodiment, the term refers to administration within 4 days of the otherset of implants. In another embodiment, the term refers toadministration within one week of the other set of implants. In anotherembodiment, the term refers to administration within 2 weeks of theother set of implants. In another embodiment, the term refers toadministration within 3 weeks of the other set of implants. In anotherembodiment, the term refers to administration within one month of theother set of implants. In another embodiment, the term refers toadministration within 2 months of the other set of implants. Eachpossibility represents a separate embodiment of the present invention.

In another embodiment, the starter set implants enable earlierattainment of therapeutic drug levels, as provided herein (Example 16).In another embodiment, the number of implants required in the initialset of implants is reduced (relative to the maintenance set of implants)due to the present of the starter set implants, as the starter setimplants make a contribution to the drug levels that is not present atthe time of administration of the maintenance set of implants.

The ability of starter sets to enable more rapid release was shown inthe present invention, by comparing the release profiles of thesingle-polymer design to the multiple-polymer design. Higher serumlevels were observed in early time points with the multiple-polymerdesign (FIGS. 1 and 3A).

In another embodiment, instead of administering a starter set ofimplants with the initial implantation, the number of implants isincreased (relative to the maintenance set of implants) to attaintherapeutic levels more quickly.

In another embodiment, the step of administering the initial set ofimplants is reversible. In another embodiment, the step of administeringthe starter set of implants is reversible. “Reversible,” in oneembodiment, refers to the ability to remove the remains of the set ofimplants by surgical or other means. In one embodiment, “reversible”refers to the ability to remove the remains of one or more of theimplants. In another embodiment, “reversible” refers to the ability toremove the majority of the remains of the set of implants. In anotherembodiment, “reversible” refers to the ability to remove the majority ofthe remains of one or more of the implants. Each possibility representsa separate embodiment of the present invention.

In one embodiment, the subject of methods of the present invention ishuman. In another embodiment, the subject is a primate. In anotherembodiment, the subject is a mammal. In another embodiment, the subjectis a rodent. In another embodiment, the subject is a laboratory animal.In another embodiment, the subject is a domestic animal. In anotherembodiment, the subject is a male. In another embodiment, the subject isa female. In another embodiment, the subject is any other type ofsubject known in the art. Each possibility represents a separateembodiment of the present invention.

In other embodiments, the individual implants of any of the setsdescribed above have any of the lengths of an implant of the presentinvention. In other embodiments, the individual implants have a combinedlength equal to any of the lengths of an implant of the presentinvention.

In another embodiment, the step of administering the individual implantsof any of the above sets is reversible. In another embodiment, the stepof administering any of the above sets is reversible. In one embodiment,“reversible” refers to one of the meanings provided above. Eachpossibility represents a separate embodiment of the present invention.

In other embodiments the individual implants of any of the above setshave any of the diameters of an implant of the present invention. Inother embodiments, the individual implants have a combined length equalto any of the diameters of an implant of the present invention.

In other embodiments, the individual implants of any of the above setshave any of the SA:V ratios of an implant of the present invention. Inother embodiments, the individual implants have a combined length equalto any of the SA:V ratios of an implant of the present invention.

In other embodiments, the individual implants of any of the above setshave any of the masses of an implant of the present invention. In otherembodiments, the individual implants have a combined length equal to anyof the masses of an implant of the present invention.

In another embodiment, the individual implants of any of the above setsare combined into a single structure (e.g. a rod-shaped structure, abundle, etc.). In another embodiment, the structure has any of thelengths of an implant of the present invention. In another embodiment,the structure has any of the diameters of an implant of the presentinvention. In another embodiment, the structure has any of the SA:Vratios of an implant of the present invention. In another embodiment,the structure has any of the masses of an implant of the presentinvention. In another embodiment, the structure enables reduction of thenumber of structures implanted. Each possibility represents a separateembodiment of the present invention.

In other embodiments, the individual biodegradable implants of any ofthe sets described above have any of the characteristics of an implantof the present invention. Each characteristic represents a separateembodiment of the present invention.

In another embodiment a method of the present invention furthercomprises administration of the therapeutic drug by a different route,together with the initial administration of implants, in order to reachand maintain therapeutic drug levels until the rate of release of theimplants is sufficient. In another embodiment, a different drug with asimilar therapeutic effect is administered with the initial set ofimplants. Any route of administration known in the art may be used. Eachroute represents a separate embodiment of the present invention.

In another embodiment, the present invention provides a method forreleasing a therapeutic drug at a substantially linear rate for a periodof several months into a body tissue of a subject, comprisingadministering to the subject an implant or set of implants of thepresent invention, thereby releasing a therapeutic drug at asubstantially linear rate for a period of several months into a bodytissue of a subject.

In another embodiment, the present invention provides a method forreleasing thiothixene at a substantially linear rate for a period ofseveral months into a body tissue of a subject, comprising administeringto the subject a thiothixene-containing implant of the presentinvention, thereby releasing thiothixene at a substantially linear ratefor a period of several months.

In another embodiment, the present invention provides a method forreleasing haloperidol at a substantially linear rate for a period ofseveral months into a body tissue of a subject, comprising administeringto the subject a haloperidol-containing implant of the presentinvention, thereby releasing haloperidol at a substantially linear ratefor a period of several months.

In another embodiment, the present invention provides a method forreleasing HCTZ at a substantially linear rate for a period of severalmonths into a body tissue of a subject, comprising administering to thesubject a HCTZ-containing implant of the present invention, therebyreleasing HCTZ at a substantially linear rate for a period of severalmonths.

In another embodiment, the present invention provides a method forreleasing ibuprofen at a substantially linear rate for a period ofseveral months into a body tissue of a subject, comprising administeringto the subject an ibuprofen-containing implant of the present invention,thereby releasing ibuprofen at a substantially linear rate for a periodof several months.

In another embodiment, the present invention provides a method forreleasing aspirin at a substantially linear rate for a period of severalmonths into a body tissue of a subject, comprising administering to thesubject an aspirin-containing implant of the present invention, therebyreleasing aspirin at a substantially linear rate for a period of severalmonths.

In another embodiment, the present invention provides a method forreleasing corticosterone at a substantially linear rate for a period ofseveral months into a body tissue of a subject, comprising administeringto the subject a corticosterone-containing implant of the presentinvention, thereby releasing corticosterone at a substantially linearrate for a period of several months.

“Several months” refers, in various embodiments, to any time period ofthe present invention. Each time period represents a separate embodimentof the present invention.

In another embodiment, the present invention provides a method forreleasing a therapeutic drug at a substantially linear rate for a periodof several weeks into a body tissue of a subject, comprisingadministering to the subject an implant or set of implants of thepresent invention, thereby releasing a therapeutic drug at asubstantially linear rate for a period of several weeks into a bodytissue of a subject.

The therapeutic drug is, in various embodiments, any therapeutic drug ofthe present invention. Each drug represents a separate embodiment of thepresent invention.

In one embodiment, the substantially linear rate of methods andcompositions of the present invention is the release rate of the implantduring the steady state phase of release. “Steady state,” in oneembodiment, refers to the period of time during which an implantexhibits a substantially linear release rate, as exemplified herein inExample 10.

In one embodiment, the substantially linear rate is 0.1 mg/day. Inanother embodiment, the rate is 0.2 mg/day. In another embodiment, therate is 0.3 mg/day. In another embodiment, the rate is 0.4 mg/day. Inanother embodiment, the rate is 0.5 mg/day. In another embodiment, therate is 0.6 mg/day. In another embodiment, the rate is 0.8 mg/day. Inanother embodiment, the rate is 1 mg/day. In another embodiment, therate is 1.2 mg/day. In another embodiment, the rate is 1.5 mg/day. Inanother embodiment, the rate is 1.8 mg/day. In another embodiment, therate is 2.0 mg/day. In another embodiment, the rate is 2.5 mg/day. Inanother embodiment, the rate is 3 mg/day. In another embodiment, therate is 3.5 mg/day. In another embodiment, the rate is 4 mg/day. Inanother embodiment, the rate is 5 mg/day. In another embodiment, therate is 6 mg/day. In another embodiment, the rate is 7 mg/day. Inanother embodiment, the rate is 8 mg/day. In another embodiment, therate is 10 mg/day. Each rate represents a separate embodiment of thepresent invention.

In another embodiment, the rate is between about 0.1-0.3 mg/day. Inanother embodiment, the rate is from 0.2-0.4 mg/day. In anotherembodiment, the rate is from 0.3-0.5 mg/day. In another embodiment, therate is from 0.4-0.6 mg/day. In another embodiment, the rate is from0.5-0.7 mg/day. In another embodiment, the rate is from 0.6-0.8 mg/day.In another embodiment, the rate is from 0.7-0.9 mg/day. In anotherembodiment, the rate is from 0.8-1.0 mg/day. In another embodiment, therate is from 0.1-0.4 mg/day. In another embodiment, the rate is from0.2-0.5 mg/day. In another embodiment, the rate is from 0.3-0.6 mg/day.In another embodiment, the rate is from 0.4-0.7 mg/day. In anotherembodiment, the rate is from 0.5-0.8 mg/day. In another embodiment, therate is from 0.6-0.9 mg/day. In another embodiment, the rate is from0.8-1.1 mg/day. In another embodiment, the rate is from 1.0-1.3 mg/day.In another embodiment, the rate is from 1.5-1.8 mg/day. In anotherembodiment, the rate is from 0.1-0.5 mg/day. In another embodiment, therate is from 0.2-0.6 mg/day. In another embodiment, the rate is from0.3-0.7 mg/day. In another embodiment, the rate is from 0.4-0.8 mg/day.In another embodiment, the rate is from 0.5-0.9 mg/day. In anotherembodiment, the rate is from 0.6-1.0 mg/day. In another embodiment, therate is from 0.8-1.2 mg/day. In another embodiment, the rate is from1.0-1.4 mg/day. In another embodiment, the rate is from 1.5-1.9 mg/day.In another embodiment, the rate is from 2-2.4 mg/day. In anotherembodiment, the rate is from 0.1-0.6 mg/day. In another embodiment, therate is from 0.2-0.7 mg/day. In another embodiment, the rate is from0.3-0.8 mg/day. In another embodiment, the rate is from 0.5-1.0 mg/day.In another embodiment, the rate is from 0.6-1.1 mg/day. In anotherembodiment, the rate is from 0.8-1.3 mg/day. In another embodiment, therate is from 1.0-1.5 mg/day. In another embodiment, the rate is from1.5-2 mg/day. In another embodiment, the rate is from 2-2.5 mg/day. Inanother embodiment, the rate is from 2.5-3 mg/day. In anotherembodiment, the rate is from 3-3.5 mg/day. In another embodiment, therate is from 3.5-4 mg/day. In another embodiment, the rate is from 4-4.5mg/day. In another embodiment, the rate is from 0.3-1.3 mg/day. Inanother embodiment, the rate is from 0.5-1.5 mg/day. In anotherembodiment, the rate is from 0.8-1.8 mg/day. In another embodiment, therate is from 1.0-2 mg/day. In another embodiment, the rate is from1.5-2.5 mg/day. In another embodiment, the rate is from 2-3 mg/day. Inanother embodiment, the rate is from 2.5-3.5 mg/day. In anotherembodiment, the rate is from 3-4 mg/day. In another embodiment, the rateis from 3.5-4.5 mg/day. In another embodiment, the rate is from 4-5mg/day. In another embodiment, the rate is from 0.5-2 mg/day. In anotherembodiment, the rate is from 1.0-2.5 mg/day. In another embodiment, therate is from 1.5-3 mg/day. In another embodiment, the rate is from 2-3.5mg/day. In another embodiment, the rate is from 2.5-4 mg/day. In anotherembodiment, the rate is from 3-4.5 mg/day. In another embodiment, therate is from 3.5-5 mg/day. In another embodiment, the rate is from0.5-2.5 mg/day. In another embodiment, the rate is from 1-3 mg/day. Inanother embodiment, the rate is from 1.5-3.5 mg/day. In anotherembodiment, the rate is from 2-4 mg/day. In another embodiment, the rateis from 2.5-4.5 mg/day. In another embodiment, the rate is from 3-5mg/day. In another embodiment, the rate is from 1-4 mg/day. In anotherembodiment, the rate is from 1.5-4.5 mg/day. In another embodiment, therate is from 2-5 mg/day. In another embodiment, the rate is from 3-6mg/day.

Each of the above rates represents a separate embodiment of the presentinvention.

In another embodiment, the present invention provides a method forreleasing risperidone at a substantially linear rate for a period of atleast 1 month into a body tissue of a subject, comprising administeringto the subject a risperidone-containing implant or set of implants ofthe present invention, thereby releasing risperidone at a substantiallylinear rate for a period of at least 1 month into a body tissue of asubject.

In another embodiment, the present invention provides a method forreleasing risperidone at a substantially linear rate for a period of atleast 2 months into a body tissue of a subject, comprising administeringto the subject a risperidone-containing implant or set of implants ofthe present invention, thereby releasing risperidone at a substantiallylinear rate for a period of at least 2 months into a body tissue of asubject.

In another embodiment, the present invention provides a method forreleasing risperidone at a substantially linear rate for a period of atleast 3 months into a body tissue of a subject, comprising administeringto the subject a risperidone-containing implant or set of implants ofthe present invention, thereby releasing risperidone at a substantiallylinear rate for a period of at least 3 months into a body tissue of asubject.

In another embodiment, the present invention provides a method forreleasing risperidone at a substantially linear rate for a period of atleast 4 months into a body tissue of a subject, comprising administeringto the subject a risperidone-containing implant or set of implants ofthe present invention, thereby releasing risperidone at a substantiallylinear rate for a period of at least 4 months into a body tissue of asubject.

In another embodiment, the present invention provides a method forreleasing risperidone at a substantially linear rate for a period of atleast 5 months into a body tissue of a subject, comprising administeringto the subject a risperidone-containing implant or set of implants ofthe present invention, thereby releasing risperidone at a substantiallylinear rate for a period of at least 5 months into a body tissue of asubject.

In another embodiment, the present invention provides a method forreleasing risperidone at a substantially linear rate for a period of atleast 6 months into a body tissue of a subject, comprising administeringto the subject arisperidone-containing implant or set of implants of thepresent invention, thereby releasing risperidone at a substantiallylinear rate for a period of at least 6 months into a body tissue of asubject.

In another embodiment, the present invention provides a method forreleasing risperidone at a substantially linear rate for a period of atleast 7 months into a body tissue of a subject, comprising administeringto the subject arisperidone-ontaining implant or set of implants of thepresent invention, thereby releasing risperidone at a substantiallylinear rate for a period of at least 7 months into a body tissue of asubject.

In another embodiment, the present invention provides a method forreleasing risperidone at a substantially linear rate for a period of atleast 8 months into a body tissue of a subject, comprising administeringto the subject a risperidone-containing implant or set of implants ofthe present invention, thereby releasing risperidone at a substantiallylinear rate for a period of at least 8 months into a body tissue of asubject.

In another embodiment, the present invention provides a method forreleasing risperidone at a substantially linear rate for a period of atleast 9 months into a body tissue of a subject, comprising administeringto the subject a risperidone containing implant or set of implants ofthe present invention, thereby releasing risperidone at a substantiallylinear rate for a period of at least 9 months into a body tissue of asubject.

In another embodiment, the present invention provides a method forreleasing risperidone at a substantially linear rate for a period of atleast 10 months into a body tissue of a subject, comprisingadministering to the subject a risperidone-containing implant or set ofimplants of the present invention, thereby releasing risperidone at asubstantially linear rate for a period of at least 10 months into a bodytissue of a subject.

In another embodiment, the present invention provides a method forreleasing risperidone at a substantially linear rate for a period of atleast 11 months into a body tissue of a subject, comprisingadministering to the subject arisperidone-containing implant or set ofimplants of the present invention, thereby releasing risperidone at asubstantially linear rate for a period of at least 11 months into a bodytissue of a subject.

In another embodiment, the present invention provides a method forreleasing risperidone at a substantially linear rate for a period of atleast 12 months into a body tissue of a subject, comprisingadministering to the subject a risperidone-containing implant or set ofimplants of the present invention, thereby releasing risperidone at asubstantially linear rate for a period of at least 12 months into a bodytissue of a subject.

In another embodiment, the present invention provides a method forreleasing risperidone at a substantially linear rate for a period of atleast 14 months into a body tissue of a subject, comprisingadministering to the subject a risperidone-containing implant or set ofimplants of the present invention, thereby releasing risperidone at asubstantially linear rate for a period of at least 14 months into a bodytissue of a subject.

In another embodiment, the present invention provides a method forreleasing risperidone at a substantially linear rate for a period of atleast 16 months into a body tissue of a subject, comprisingadministering to the subject a risperidone-containing implant or set ofimplants of the present invention, thereby releasing risperidone at asubstantially linear rate for a period of at least 16 months into a bodytissue of a subject.

In another embodiment, the present invention provides a method forreleasing risperidone at a substantially linear rate for a period of atleast 18 months into a body tissue of a subject, comprisingadministering to the subject a risperidone-containing implant or set ofimplants of the present invention, thereby releasing risperidone at asubstantially linear rate for a period of at least 18 months into a bodytissue of a subject.

In another embodiment, the present invention provides a method fortreating a schizophrenia in a human, comprising administering to thehuman an implant or set of implants of the present invention, therebytreating a schizophrenia in a human.

In one embodiment, the schizophrenia is catatonic schizophrenia. Inanother embodiment, the schizophrenia is paranoid schizophrenia. Inanother embodiment, the schizophrenia is disorganized schizophrenia. Inanother embodiment, the schizophrenia is undifferentiated schizophrenia.In another embodiment, the schizophrenia is residual schizophrenia. Inanother embodiment, the schizophrenia is negative or deficitschizophrenia. In another embodiment, the schizophrenia is a psychosis.In another embodiment, the schizophrenia is any other type ofschizophrenia known in the art. Each possibility represents a separateembodiment of the present invention.

As provided herein, methods of the present invention are effective inextended delivery of risperidone and in treatment of schizophrenia(Examples 8-9). In vivo risperidone serum concentration was within thetarget range of 2-15 ng/ml (Foster R H and Goa K L (1998)Pharmacoeconomics 14: 97-133) for a substantial portion of the releaseinterval (FIGS. 1 and 3).

In another embodiment, the present invention provides a method fortreating a bipolar disorder in a human, comprising administering to thehuman an implant or set of implants of the present invention, therebytreating a bipolar disorder in a human.

In another embodiment, the present invention provides a method fortreating a dementia in a human, comprising administering to the human animplant or set of implants of the present invention, thereby treating adementia in a human.

In another embodiment, the present invention provides a method fortreating delirium in a human, comprising administering to the human animplant or set of implants of the present invention, thereby treatingdelirium in a human.

In another embodiment, the present invention provides a method fortreating agitation in a human, comprising administering to the human animplant or set of implants of the present invention, thereby treatingagitation in a human.

In another embodiment, the present invention provides a method fortreating an impulse control disorder in a human, comprisingadministering to the human an implant or set of implants of the presentinvention, thereby treating an impulse control disorder in a human.

In another embodiment, the present invention provides a method fortreating a psychotic depression in a human, comprising administering tothe human an implant or set of implants of the present invention,thereby treating a psychotic depression in a human.

In another embodiment, the present invention provides a method fortreating a schizophrenia in a human, comprising performing one of theabove methods of maintaining a therapeutic level of a drug in a subject,thereby treating a schizophrenia in a human.

In another embodiment, the present invention provides a method fortreating a bipolar disorder in a human, comprising performing one of theabove methods of maintaining a therapeutic level of a drug in a subject,thereby treating a bipolar disorder in a human.

In another embodiment, the present invention provides a method fortreating a dementia in a human, comprising performing one of the abovemethods of maintaining a therapeutic level of a drug in a subject,thereby treating a dementia in a human.

In another embodiment, the present invention provides a method fortreating delirium in a human, comprising performing one of the abovemethods of maintaining a therapeutic level of a drug in a subject,thereby treating delirium in a human.

In another embodiment, the present invention provides a method fortreating agitation in a human, comprising performing one of the abovemethods of maintaining a therapeutic level of a drug in a subject,thereby treating agitation in a human.

In another embodiment, the present invention provides a method fortreating an impulse control disorder in a human, comprising performingone of the above methods of maintaining a therapeutic level of a drug ina subject, thereby treating an impulse control disorder in a human.

In another embodiment, the present invention provides a method fortreating a psychotic depression in a human, comprising performing one ofthe above methods of maintaining a therapeutic level of a drug in asubject, thereby treating a psychotic depression in a human.

In another embodiment, the present invention provides a use of animplant or set of implants of the present invention for the preparationof a pharmaceutical composition for treating schizophrenia. In anotherembodiment, the present invention provides a composition comprising animplant or set of implants of the present invention for the treatment ofschizophrenia.

In another embodiment, the present invention provides a use of animplant or set of implants of the present invention for the preparationof a pharmaceutical composition for treating bipolar disorder. Inanother embodiment, the present invention provides a compositioncomprising an implant or set of implants of the present invention forthe treatment of bipolar disorder.

In another embodiment, the present invention provides a use of animplant or set of implants of the present invention for the preparationof a pharmaceutical composition for treating dementia. In anotherembodiment, the present invention provides a composition comprising animplant or set of implants of the present invention for the treatment ofdementia.

In another embodiment, the present invention provides a use of animplant or set of implants of the present invention for the preparationof a pharmaceutical composition for treating delirium. In anotherembodiment, the present invention provides a composition comprising animplant or set of implants of the present invention for the treatment ofdelirium.

In another embodiment, the present invention provides a use of animplant or set of implants of the present invention for the preparationof a pharmaceutical composition for treating agitation. In anotherembodiment, the present invention provides a composition comprising animplant or set of implants of the present invention for the treatment ofagitation.

In another embodiments the present invention provides a use of animplant or set of implants of the present invention for the preparationof a pharmaceutical composition for treating an impulse controldisorder. In another embodiment, the present invention provides acomposition comprising an implant or set of implants of the presentinvention for the treatment of an impulse control disorder.

In another embodiment, the present invention provides a use of animplant or set of implants of the present invention for the preparationof a pharmaceutical composition for treating psychotic depression. Inanother embodiment, the present invention provides a compositioncomprising an implant or set of implants of the present invention forthe treatment of psychotic depression.

The period of treatment of any of the above diseases provided by amethod of the present invention may be any of the time periods of thepresent invention. Each period represents a separate embodiment of thepresent invention.

“Treating,” in one embodiment, refers to therapeutic intervention. Inanother embodiment, the term refers to prophylactic intervention. Inanother embodiment, the term refers to ameliorating the symptoms of adisease or disorder. In another embodiment, the term refers toameliorating a symptoms, disease or disorder secondary to the disease ordisorder being treated. In another embodiment, “treating” refers toslowing the progression of a disease. Each possibility represents aseparate embodiment of the present invention.

Methods for diagnosing and assessing the severity of the above disordersare well known in the art, and are described, for example, in theDiagnostic and Statistical Manual of Mental Disorders (DSM), publishedby the American Psychiatric Association, Washington D.C. Each methodrepresents a separate embodiment of the present invention. In anotherembodiment, schizophrenia or another of the above disorders is diagnosedby a method described above in the description of methods of assessingthe efficacy of risperidone therapy.

Methods of assessing the efficacy of risperidone therapy in animals andhumans are well known in the art. In animals efficacy of risperidonetherapy may be assessed by, for example, PPI (described below) locomotoractivity, rotarod, and catalepsy assessments. Locomotor activity is, inone embodiment, measured in a “home cage” activity monitoring system(MedAssociates, St. Albans, Vt.). This system allows for a standard,clean home cage to be placed in a photobeam frame with two levels ofsensors arranged in an 8-beam array strip with 1.25 inch spacing. Acomputer detection system monitors interruptions of the photobeams forthe ambulations parameter. Total ambulations are determined by thenumber of photobeam interruptions the animal makes while moving aboutthe cage. Data are recorded on Med Associates personal computer-designedsoftware and monitored e.g. at 5-minute intervals for a total of 30minutes per activity monitoring session. Rats typically receive severaldays of habituation to the apparatus and task prior to their firstexposure to amphetamine.

In another embodiment, rotarod is used to assess the efficacy ofrisperidone therapy. In one embodiment, the accelerating rotarodtreadmill apparatus (Stoelting Co., Wood Dale, Ill.) is used todetermine motor function. Rats are placed on the stationary rod in orderto acclimate to the apparatus. The speed is then set to graduallyincrease from 2 to 20 rpm. The maximal score in maintaining equilibriumand posture is fixed (e.g. 5 minutes; Lelas S, Wong H et al, J PharmacolExp Ther 309: 293-302, 2004). Testing ends after the period or when theanimal falls off of the rod.

In another embodiment, catalepsy assessment is used to assess theefficacy of risperidone therapy. Catalepsy is tested in animals (e.g.rats) to assess motor effects from risperidone implants. Rats arepositioned with their fore legs against a cage side, and the amount oftime required to resume a normal posture is recorded. Increased latencyto resume normal position with all four legs on the bottom of the cageis interpreted as indicative of motor impairment secondary torisperidone.

In another embodiment, the acoustic startle response is used to assessthe efficacy of risperidone therapy. The acoustic startle response is aquantifiable, reflexive movement after a loud acoustic stimulus.Prepulse inhibition (PPI) occurs when the startle response is reducedbecause of the previous presentation of a less intense sensory stimulus(Hoffman H S, Searle J L (1965) J Comp Physiol Psychol 60:53-58). PPIcan be attenuated by administration of dopamine (DA) agonists such asapomorphine (APO) and amphetamine (AMPH), and this effect is reversed bydopamine receptor antagonists such as haloperidol and risperidone(Mansbach R S, Geyer M A (1989). Neuropsychopharmacol 2: 299-308;Swerdlow N R et al, (1991). J Pharmacol Exp Ther 256: 530-536; SwerdlowN R et al, Neuropsychopharmacol 18: 50-56). As such, attenuation of PPIby DA receptor agonists is an effective animal model for the deficits insensory-gating processes observed in schizophrenia (Braff D L, Geyer M A(1990) Arch Gen Psychiatry 47: 181-188).

Methods for recording of auditory evoked potentials are well known inthe art. In one embodiment, recording of auditory evoked potentials isachieved via stereotaxic implantation of tripolar electrode assemblies.In another embodiment, these assemblies are used for non-anesthetizedrecording of auditory evoked potentials. These methods are well known inthe art and are described, e.g, in (Connolly et al., 2003; Connolly etal., 2004; Maxwell et al., 2004; Siegel et al., 2005).

An additional method for assessment of risperidone efficacy in animalsis behavioral observations, which are well known in the art and aredescribed, for example, Elmer G I, Brockington A et al (Cocainecross-sensitization to dopamine uptake inhibitors: unique effects ofGBR12909. Pharmacol Biochem Behav 53: 911-918, 1996). For example, thefollowing behaviors are observed and scored for their presence orabsence during each 5-min interval: still; sniffing; licking; gnawing;grooming; locomotion (all four legs moving); rearing (both front feetoff the cage floor); head down (animal standing, walking or running withits nose below horizontal for more than 5 seconds); swaying (rhythmicswaying movements of the animal's head or body for more than 3 seconds);circling (walking or running in a continuous circle for more than 5seconds).

In another embodiment, the efficacy of risperidone therapy is assessedby quantification of dopamine D₂ and/or serotonin 5HT_(1A/2A/2C)receptor expression in brain samples (e.g. cortex, hippocampus, striatumand/or cerebellum). Risperidone increases dopamine D₂ receptorexpression and decreases serotonin 5HT_(1A/2A/2C) receptor expression.Serotonin receptor Western blots can utilize polyclonal antibodiesAB5406 (Chemicon, Temecula, Calif.), PC176L (Calbiochem, Calif.), or andAB5655 (Chemicon). D₂ receptor Western blots can utilize polyclonalantibody WR-3526, (Research and Diagnostic Antibodies, Berkeley,Calif.). Each possibility represents a separate embodiment of thepresent invention.

Methods of assessing the efficacy of risperidone therapy in humans aredescribed, e.g, in Heresco-Levy U et al (Biol Psychiatry 2005 57(6):577-85), Moller H J et al (Int Clin Psychopharmacol. 2005 20(3):121-30); and Hirschfeld R M et al (Arn J Psychiatry. 2004 161(6):1057-65). In another embodiment,the efficacy of risperidone therapy inhumans by assessing the severity of the disorder for which risperidonewas described, using the DSM-IV. Each of the above methods for assessingefficacy of risperidone therapy in animals may be utilized for humansand vice-versa.

Each of the above methods for assessment of risperidone efficacyrepresents a separate embodiment of the present invention.

In another embodiment, the present invention provides an implant havinga drug load of a therapeutic drug between about 20-30% by mass,inclusive, and between 70%-80% by mass, inclusive, of a polymer, thepolymer comprising PLA and optionally PGA in a PLA:PGA ratio between80:20 and 100:0 by mass, inclusive, the implant having a radius of R₀according to the equation:

$\left( \frac{\mathbb{d}M_{d}}{\mathbb{d}t} \right) = {4\pi\;{R_{0}^{2}\left( {1 - {\frac{C_{w}\sqrt{D}}{2R_{0}\sqrt{k}}}} \right)}^{2}\frac{C_{w}\sqrt{D}{{erf}\left\lbrack \sqrt{kt} \right\rbrack}}{2\sqrt{k}}}$

-   -   wherein:    -   “erf(x)” refers to

${\frac{2}{\sqrt{}}{\int_{0}^{x}{{\mathbb{e}}^{{- t}\; 2}\ {\mathbb{d}t}}}};$

-   -   dM_(d)/dt is the desired steady-state release rate of        therapeutic drug at time t, D is the diffusion coefficient of        water into the matrix, k is the reaction rate and C_(w) is the        concentration of water in the implant at time t;    -   wherein k is determined by the formula:

$\frac{\partial c_{w}}{\partial t} = {{D{\nabla^{2}c_{w}}} - {kc}_{w}}$

-   -   wherein S is the solubility of therapeutic drug in water; and        wherein k is a constant between about 0.05-0.33.

In one embodiment, the therapeutic drug contained in the above implantis risperidone. In another embodiment, the therapeutic drug ishaloperidol, in which case D is 1.7×10^−10, and k is 0.07 (Example 10).In another embodiment, the therapeutic drug is thiothixene, in whichcase D is 9×10^−10, and k is 0.06. In another embodiment, thetherapeutic drug is HCTZ, in which case D is 2.1×10^−6, and k is 0.26.In another embodiment, the therapeutic drug is corticosterone, in whichcase D is 2.5×10^−7, and k is 0.33. In another embodiment, thetherapeutic drug is ibuprofen, in which case D is 7.0×10^−6, and k is0.16. In another embodiment, the therapeutic drug is aspirin, in whichcase D is 8.0×10{circumflex over (0)}−2, and k is 0.06. In anotherembodiment, the therapeutic drug is any other therapeutic drug known inthe art. Each possibility represents a separate embodiment of thepresent invention.

In another embodiment, k, the degradation reaction rate coefficient,depends on the drug properties as given by a combination of the drugsolubility and the presence of OH groups (Example 11). For drugs withthe same water solubility, the rate of polymer hydrolysis increases withthe density of OH groups, while for drugs with the same OH group densityk decreases with solubility

in another embodiment, k is empirically determined, as described inExample 10.

In another embodiment, the presence of the drug affects the polymerdegradation rate. In one embodiment, the drug affects the polymerdegradation rate by affecting the diffusion of water into the polymericmatrix. In another embodiment, the drug affects the polymer degradationrate by affecting the rate of the degradation reaction. In anotherembodiment, the drug affects the polymer degradation rate by acombination of the above mechanisms. Each possibility represents aseparate embodiment of the present invention.

In another embodiment, the present invention provides a method ofdesigning an implant to deliver a target rate of release of atherapeutic drug, by utilizing an equation of the present invention(e.g. equation 4, 5a, or 5b).

In another embodiment, the present invention provides a method ofdesigning an implant to achieve a target rate serum concentration of atherapeutic drug, by utilizing an equation of the present invention(e.g. equation 8, 9, or 10; Example 12).

In another embodiment, the present invention provides a method ofachieving a drug release rate dM_(d)/dt at time t, comprisingadministering an implant whose radius has been determined using anequation of the present invention (e.g. equation 4, 5a, or 5b).

In another embodiment, the present invention provides a method ofachieving a serum concentration x at time t, comprising administering animplant whose radius has been determined using an equation of thepresent invention (e.g. equation 8, 9, or 10).

Any of the methods of the present invention may utilize any of theimplants of the present invention. Each combination of a method of thepresent invention with an implant of the present invention represents aseparate embodiment of the present invention.

In another embodiment, the present invention provides a kit comprising areagent utilized in performing a method of the present invention. Inanother embodiment, the present invention provides a kit comprising animplant of the present invention.

EXPERIMENTAL DETAILS SECTION Example 1 Extended Haloperidol Release fromPLGA Implants in Monkeys Materials and Experimental Methods

Subjects

Two monkeys (Macaca fascicularis, Rangos Research Facility) wereutilized, each of which received 6 copolymer PLGA(poly(d,1-lactic-glycolic acid))-containing implants. For theexperimental monkey, the implants contained 40% haloperidol by mass,with the other 60% consisting of one of the PLGA polymers depicted inTable 2 below. The implants administered to the control monkey contained100% of the PLGA polymers depicted in Table 2. PLGA polymers wereprovided by Medisorb® Alkermes, (Cincinnati, Ohio). Haloperidol dosingaveraged 1 mg/kg/day over 12 months to achieve a serum concentration of2-10 ng/ml.

TABLE 2 Polylactic acid:polyglycolic acid (PLA:PGA) molar ratios andinherent viscosities of the PLGA polymers in the implants used in theprimate experiment. Inherent viscosities in the table are expressed inunits of dl/g in chloroform, and were measured at 30° C., 0.5 dl/g usinga size 25 Cannon-Fenske glass capillary viscometer. Implant numberPLA:PGA molar ratio Inherent viscosity (IV) 1 75:25 0.66-0.80 2 85:150.66-0.80 3 90:10 High (0.87) 4 90:10 Low (0.68) 5 95:5  0.66-0.80 6100:0  0.66-0.80Implant Manufacture

Polymers and haloperidol (Sigma, St. Louis, Mo.) were mixed in aproportion of 60/40 by mass and solvent cast from acetone (FisherScientific, Pittsburgh, Pa.). The resulting film was compression moldedto disk-shaped implants of 20 mm diameter with average thickness of1.22±0.0 mm, mass 493±2 mg and density of 1.28±0.0 g/cc.

Pharmacokinetic Determination:

Blood was drawn twice per month. Blood was centrifuged and serum frozenat −80° C. until analysis. Serum risperidone and 9-OH risperidoneconcentrations were determined in duplicate at each time point for eachanimal. Specimens were separated by centrifugation and haloperidollevels were assayed by high-pressure liquid chromatography (HPLC) withultraviolet (UV) detection (FIG. 1). Assays from control animals yieldeddrug levels of zero.

Results

As depicted in FIG. 1, haloperidol release was measured over a total of443 days. Mean serum concentration was 10.5±1.5 ng/ml during the first224 days, with the exception of one value (27.1 ng/ml on day 40). Duringthe subsequent 176 days, serum haloperidol levels were sustained at alower mean concentration of 4.0±0.4 ng/ml. Levels decreased during thelast 45 days of the study (mean serum concentration 1.2±0.3 ng/ml).

Thus, 14 months of haloperidol release was achieved in monkeys usingbiodegradable implants.

Example 2 Extended Haloperidol Release from PLGA Implants in RabbitsMaterials and Experimental Methods

Experimental Design

Two implant systems were tested, the first containing five differentsingle-polymer implants (similar to Example 1), and the secondcontaining five implants comprised of a single polymer. The aim of thesingle-polymer model was to reduce the initial spike while maintainingrelease for one year.

Subjects

Rabbits (N=12, Covance, Denver, Pa.) ranged from 4.0 to 5.7 kg. Fiveanimals received implants composed of a single polymer, 100% PLA, with40% haloperidol load for a total drug content of 418±7 mg/kg, yielding adaily dose of 1.13±0.02 mg/kg/day for anticipated delivery of 365 days.Five additional animals received implants of a combined-polymer systemincluding 75:25, 85:15, 90:10 high IV, 90:10 low IV and 100:0 PLGA. Themean dose in this group was 473±4 mg/kg with an expected delivery of 365days, yielding a mean dose of 1.29±0.03 mg/kg/day. Two rabbits receivedimplants without drug as a control. One control received 100% PLAimplants to mimic the single-polymer condition, the other receivedimplants composed of 75:25, 85:15, 90:10 high IV, 90:10 low IV & 100:0PLGA to mirror the combined-polymer system.

Implant Manufacture

Implants were made using procedures described in Example 1, in this casewith an average mass of 536±2 mg and density of 1.24±0.00 g/cc. Implantswere tethered to assist in locating implant sites at necropsy.

Pharmacokinetic Determination

Solid phase extraction (SPE) was performed using the Waters 20-postionSPE vacuum manifold and Waters Oasis MCX SPE cartridges, (3 ml/60 μgcartridges). Cartridges were conditioned with methanol and water,samples containing 2% phosphoric acid were loaded, then cartridges werewashed with 5% methanol in 0.1 N hydrochloric acid, then 100%acetonitrile, then eluted with 5% NH₄OH in 100% acetonitrile. Sampleswere dried under nitrogen in an 80° C. water bath, reconstituted in 100μl of mobile phase, vortexed, and centrifuged for 5 minutes. 75 μl ofthe reconstituted samples were loaded into an autosampler and 50 μl wasinjected. HPLC was performed using a Waters XTerra RP 18 5 μm, 4.6×150mm column, flow rate 1.0 ml/min, run time 30 min. Mobile phase andsample buffer were composed of 55% H₂O with 35% acetonitrile and 10% 100mM ammonium bicarbonate, pH 10. Peaks were detected at a wavelength of280 nm. Standard solutions of risperidone and 9-OH risperidone wereprepared in normal rat serum (range 1.25-50 ng/ml), extracted, andincluded within each run to provide the standard curve and retentiontime for each compound. The retention times for risperidone and 9-OHrisperidone were 8.6 and 5.9 min, respectively.

Histopathology

Five rabbits were sacrificed after nine months to obtain interimpathological analyses, with remaining seven rabbits sacrificed after anadditional four months. Remains of implants were found tethered in placein all animals that received implants (FIG. 2). Implants did not causecapsule formation, leading to a simple removal process. HPLC/UV and NMRspectroscopy confirmed the presence of haloperidol and PLGA breakdownproducts in residual implants. Histological analyses showed all organsystems in all rabbits were within normal limits.

Results

A similar experiment was performed in rabbits, in this case comparingfive different single-polymer implants (similar to Example 1) with fiveimplants comprised of a single polymer. Rabbits administered themultiple-polymer system had haloperidol levels of 4.0±0.6 ng/ml over 360days. An initial period of higher concentration occurred during thefirst 198 days (mean serum level of 6.1±0.7 ng/ml) (FIG. 3A). Levelsthen tapered to a mean of 1.1±0.3 ng/ml through 320 days, dropping belowthe level of detection at 360 days. B) Rabbits administered thesingle-polymer system exhibited a more symmetric release profile and hada mean serum concentration of 2.5±0.4 ng/ml, dropping below the level ofdetection at 360 days, as observed for the multiple-polymer system (FIG.3B).

Thus, the findings obtained with rabbits confirmed the monkey findings,showing that 12 months of haloperidol release can be achieved usingbiodegradable implants. These results also show that at least in somecases, a more symmetric release profile can be achieved with asingle-polymer system than with a multiple-polymer system.

Example 3 Effect of Implant Geometry on Release Rate Materials andExperimental Methods

Implants containing 40% Haloperidol and 60% of a 50:50 PLGA polymer weremanufactured by solvent casting. Material was compression molded intodiscs or slowly extruded into rods using a high pressure piston extruder(DACA Instruments, Goleta, Calif.) at 100° C. Rods & discs were matchedfor weight. The surface area to volume (SA:V) ratios for thesegeometries are 1.92 for discs (3 mm radius, 1.6 mm thickness) and 1.56for rods (1.8 mm radius, 4.5 mm length).

To measure release profiles, implants were placed in 500 milliliter (ml)phosphate buffered saline (PBS), pH 7.0, 37° C., 40 rpm, in the dark.

Results

The effect of implant geometry (rods vs. disks) on haloperidol releasewas examined. Release profiles were nearly identical for both geometries(FIG. 4), demonstrating that rods have very similar release profiles todisks. Thus, rods-shaped implants can be used to deliver maintaintherapeutic levels of a drugs in a subject over an extended period oftime.

Example 4 Stability of Risperidone in Physiological Aqueous Solution

To evaluate the long-term stability of risperidone in physiologicalsolution, 10 mg Risperidone was dissolved in 100 μl of acetonitrile forsubsequent dissolution in 1,000 ml of PBS (0.9% NaCl, 0.01 M NaOH, 0.01M NaH₂PO₄, pH 7.0) to yield a final solution of 10,000 nanograms(ng)/ml. The solution was shaken at 40 revolutions per minute in alight-safe amber bottle at 37° C. Drug concentration of a 1-ml samplewas measured three times per week by UV spectroscopy (AmershamBiosciences, Buckinghamshire, UK). The concentration of drug exhibitedonly a slight change (1.4% over 343 days, equivalent to 0.004% per day;linear trendline: y=−0.0004x+9.777). Studies were replicated using UVspectrophotometry and HPLC (FIG. 5). There was a 0.99 correlationcoefficient between HPLC and UV spectrophotometry, indicating that theUV spectrophotometry method is an accurate method for in vitro analysisof risperidone concentration.

Thus, risperidone is stable over extended time periods in physiologicalsolution.

Example 5 Effect of PLA:PGA Ratio on Risperid One Release

Risperidone release from different polymers including 50:50, 65:35 and75:25 PLGA was evaluated to assess the effects of PLA:PGA ratio on invitro risperidone release. Implants were made as described for Example1, in this case with 20% risperidone (RBI, Flanders, N.J.) and 80% PLGA(Alkermes). Three replicates of each implant type were placed inseparate light-safe bottles of 500 ml PBS and shaken at 37° C., 40 rpm).1 ml aliquots were taken from each bottle 3 times per week and analyzedby UV spectrophotometry, after which 1 ml of buffer was reintroduced tomaintain constant volume. The 75:25 polymer exhibited the slowestrelease profile (FIG. 6A).

In an additional study, the consistency of the effect between mice wasdetermined. Eight mice were administered 75:25 PLA:PGA, 20% drug loadrisperidone implants, and the risperidone and 9-OH-risperidone serumconcentrations assessed after 42 days. Results are shown in Table 1,together with the mg/kg/day release rate, calculated by dividing theweight of the risperidone in the implant/the weight of the mouse/theestimated number of days of release (120).

TABLE 1 Top eight mice were administered risperidone-containingimplants, bottom five were administered control implants with norisperidone. Risperidone implants mouse serum 42 days after implantationRisperidone 9-OH Risperidone Concentration Concentration mouse# post daymg/kg/day (ng/ml) (ng/ml) 1648 42 2.5 6.0 5.7 1649 42 2.5 10.1 12.6 165042 3.2 5.0 7.4 1651 42 2.5 6.3 7.0 1652 42 2.6 6.2 7.1 1653 42 2.8 10.211.8 1654 42 3.2 7.0 5.2 1655 42 2.7 7.8 8.2 average 7.3 8.1 1642 42 0 00 1643 57 0 0 0 1644 42 0 0 0 1646 57 0 0 0 1647 42 0 0 0 average 0 0

Example 6 Effect of Surface Area to Volume Ratio on Risperidone ReleaseMaterials and Experimental Methods

Studies utilized 4 rods per condition with surface area to volume (SA:V)ratios of 2.75 and 6.17, both utilizing a 30% risperidone drug load,75:25% PLGA. Rods were placed in separate bottles of PBS at 37° C. at 40rpm. 0.3 ml samples were drawn 3 times per week analyzed by HPLC and UVspectrophotometry (Bio-teck Instruments, Winooski, Vt.).

Results

To determine the effect of SA:V ratio on risperidone release,risperidone release was measured from rods with identical compositionbut different SA:V ratios. The pattern of release among these 2 SA:Vratios differed during the first 44 days of release with the smallerradius rods (larger SA:V) exhibiting more rapid release (FIG. 6B). Thus,larger diameter rods, which have a smaller SA:V ratio, provide moreextended delivery than smaller diameter rods.

These results confirm and augment the results of Example 3 bydemonstrating that release from biodegradable implants is a function ofSA:V ratio, as described further below in equation (8). Thus, rods aswell as disks can be used to achieve extended release of drugs inbiodegradable implants.

Example 7 Determination of Optimal Risperidone Drug Load in Implants

To determine the optimal risperidone concentration for implants,implants were prepared using a single polymer (85:15 PLGA) combined withrisperidone at ratios of 10%, 20%, 30%, 40%, 50% or 60% drug by weight(FIG. 7). Implants each had a mass of approximately 50 mg, and thuscontained drug masses of 5, 10, 15, 20, 25 and 30 mg, respectively. Alarge fraction of the total drug load of the 10% and 60% drug-loadedimplants was released within the first 30 days, while the 20%, 30%, 40%,and 50% drug-release their risperidone more slowly. The most linearpattern of release was achieved with the 40% and 50% risperidone-loadedimplants, with similar slopes throughout the entire time tested.

Example 8 Risperidone Implants Increase PPI AND P20 Amplitude and BlockAmphetamine-Induced Disruption of N40-Evoked Potentials at 14 and 21Days Post-Implantation Materials and Experimental Methods

Risperidone implants yielded serum risperidone concentration of 7.3±0.68ng/ml (mean±SEM) and serum 9-OH risperidone of 8.1±0.95 ng/ml at 42 daysafter implantation. Brain levels were 6.2±1.45 & 4.6±0.52 ng/gm forrisperidone & 9-OH risperidone respectively. Disc shaped implants (SA:Vratio of 2.34) were made from 85:15 PLGA, 0.66-0.80 IV, with 20%risperidone drug load. Mice (C57BL/6J) received either implantscontaining risperidone (n=8) or polymer alone (n=8) prior to stereotaxicimplantation of tripolar electrode assemblies (PlasticsOne Inc.,Roanoke, Va.) for non-anesthetized recording of auditory evokedpotentials (Connolly et al., 2003; Connolly et al., 2004; Maxwell etal., 2004; Siegel et al., 2005). Studies on startle and prepulseinhibition (PPI) of the acoustic startle response were performed between14 and 21 days after implantation as described in (Gould T J et al,Sensorimotor gating deficits in transgenic mice expressing aconstitutively active form of Gs alpha. Neuropsychopharmacol 29:494-501). Recording of evoked potentials was performed 28 days afterimplantation of electrodes. Recording for the drug exposure trial begansix minutes after injection of amphetamine 2 mg/kg i.p. and was comparedto the pre-amphetamine recording session. Stimuli were generated byMicro1401 hardware and Spike 5 software (CED, Cambridge, England) andwere delivered through speakers attached to the cage top. A series of 50white noise clicks (10 ms duration) were presented in pairs 500 ms apartwith a 9 second inter-pair interval at 85 db compared to background of70 db. Waveforms were filtered between 1 and 500 Hz, baseline correctedat stimulus onset and individual sweeps were rejected for movementartifact based on a criteria of two times the root mean squaredamplitude. Average waves were created from 50 ms pre-stimulus to 200 mspost stimulus. Mice were allowed fifteen minutes to acclimate to theFaraday cage prior to stimulus onset.

Results

Mice (C57BL/6J) received either implants containing risperidone (n=8) orpolymer alone, then were subjected to non-anesthetized recording ofauditory evoked using implanted tripolar electrode assemblies. Whilerisperidone implants did not alter startle amplitude (FIG. 8A), they didincrease PPI relative to controls (FIG. 8B). In addition, risperidoneimplants increased the amplitude of P20 (the human P50 analogue) incontrol animals (FIG. 9A), and attenuated amphetamine-induced reductionof the amplitude of N40 (the human N100 analogue) (FIG. 9B).Abnormalities in the P50 and N100 components reflect abnormal neuronalarchitecture related to the generation and modulation of auditoryresponses and are informative about more generalized neurologicalimpairments in schizophrenia (Adler L E, Olincy A et al, Schizophr Bull24: 189-202, 1998; Freedman R, Adler L E et al, Harv Rev Psychiatry 2:179-192, 1994).

Example 9 Risperidone Implants Increase PPI and P20 Amplitude and BlockAmphetamine-Induced Disruption of N40-Evoked Potentials at LaterPost-Implantation Time Points

Experiments are performed to determine the effect of the risperidoneimplants of Example 8 on startle, PPI, P20, and N40, at later timepoints after implantation. In this case, significant effects areobserved for all these parameters in animals receiving the risperidoneimplants, consistent with the larger release rate and subsequentlyhigher plasma concentration attained at later time points, as shown inExamples 5-7.

Example 10 Release Rate From Hydrolysable Bio-Degradable Implants can beDetermined Based on Drug Solubility and the Rate of Degradation of theImplant Materials and Experimental Methods

Drugs

Six drugs were examined:

-   1). Thiothixene:    N,N-dimethyl-9-[3-(4-methylpiperazin-1-yl)propylidene]thioxanthene-2-sulfonamid.-   2). Haloperidol:    4-[4-(4-chlorophenyl)4-hydroxy-1-piperidyl]-1-(4-fluorophenyl)-butan-1-one.-   3). Hydrochlorothiazide (HCTZ):    9-chloro-5,5-dioxo-5λ⁶-thia-2,4-diazabicyclo[4.4.0]deca-6,8,10-triene-8-sulfonamide.-   4). Corticosterone:    11-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-1,2,6,7,8,9,10,11,12,    13,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-one.-   5). Ibuprofen: 2-[4-(2-methylpropyl)phenyl]propanoic acid.-   6). Aspirin: 2-acetyloxybenzoic acid

Properties of the drugs are listed in Table 3. All drugs were obtainedfrom Sigma-Aldrich, Inc.

TABLE 3 Properties of drugs utilized in this Example. OH group density(OH Water groups/ Molecular Molecular solubility unit Drug formulaweight (mg/mL)* D** k** mass) Haloperidol C₂₁H₂₃ClFNO₂ 375.87 0.13 1.7 *10⁻¹⁰ 0.07 2.66 * 10⁻³ Thiothixene C₂₃H₂₉N₃O₂S₂ 443.64 0.14   9 * 10⁻¹⁰0.06 0 HCTZ C₇H₈ClN₃O₄S₂ 297.75 2.00 2.1 * 10⁻⁶ 0.26 0 CorticosteroneC₂₁H₃₀O₄ 346.47 0.50 2.5 * 10⁻⁷ 0.33 5.77 * 10⁻³ Ibuprofen C₁₃H₁₈O₂206.29 0.47   7 * 10⁻⁶ 0.16 4.85 * 10⁻³ Aspirin C₉H₈O₄ 180.16 4.99   8 *10⁻² 0.06 5.55 * 10⁻³ *Measured after 14 days as described below. **k isunits of 1/day, and D dimensionless. Obtained by fitting the dataplotted in FIG. 10 to equation (4), as demonstrated in FIG. 11.Ultraviolet (UV) Scanning

Drugs were dissolved in PBS, pH 7.4, to the expected in vitrosolubility. Absorbance scans were performed on drug solutions within therange of 200 nm to 400 nm, using a blank cuvette containing salinesolution as a reference. A characteristic UV footprint was generated foreach drug, and the wavelength at which the relevant maximum peakoccurred was utilized in subsequent in vitro assays. Standard curveswere prepared for each drug in PBS so that absorbencies could beconverted to concentrations using the Lambert-Bear law.

Polymer/Drug Pellet Fabrication

400 mg of 50:50 PLGA and 100 mg of drug were solvent cast to obtain a20% by mass drug-load. Polymer and drug were dissolved in 45 milliliters(mL) acetone (Fisher Scientific, Inc.) and vortexed, then poured into anevaporation dish and placed in a vacuum oven at 40° C. under vacuum (3inches Hg) with trace airflow. After seven days, dishes were removedfrom the oven. Evaporation residue was a thin film mixture of polymerand drug with homogenous appearance. The film was carefully weighed toconfirm complete removal of solvent and pressed into four uniformdisk-shaped pellets with 1 mm thickness and 1.2 mm diameter, using aTeflon®-coated pellet press set at 25 (kilo-pounds) klb and 60° C.Pellets were carefully weighed and measured to determine densities.Negative control pellets with a 0% drug load were fabricated in the samemanner, using 500 mg polymer and no drug.

Drug Solubility in Water

Ascending mass of drug, ranging from 0.5 to 200 mg, of each drug wasmixed into a capped glass jar (Wheaton, Inc.) containing 10 to 50 mLdistilled water and subjected to moderate mixing for 14 days at 21° C.1-mL aliquots were removed at fixed time intervals and analyzed by UVSpectroscopy to determine maximum saturation concentration.

In Vitro Drug Release Assay

Assays were preformed in triplicate using three of each set of fouruniform pellets. Each pellet was added to an amber-glass, capped jar(Wheaton, Inc.) containing 500 mL of a PBS solution and subjected tomoderate shaking in the dark, at 37° C. 1-mL aliquots of were analyzedby UV Spectroscopy at fixed time intervals and. Positive control jarscontained PBS and 10 mg of drug, the expected maximum release for a 20%drug-loaded pellet with a mass of 50 mg, and were also used to determinestability of each drug in saline solution over the course of theexperiment.

Results

Release of six drugs from PLGA matrices was examined. ƒ, the fraction ofthe drug released from the pellet, is plotted in FIG. 10 as a functionof time t. At long time periods all drug was released and ƒ≈1. Precedingthis full release limit was a region wherein the release rate was fairlyconstant, as evidenced by a linear relationship between the fraction ofreleased drug (Δƒ and the time (Δt).

These results show that linear drug release can be obtained with asingle type of biodegradable polymer.

Two additional features emerge from the above drug-release measurement:First, some drugs (e.g. thiothixene) were released as soon as theexperiment begins, while others (e.g. haloperidol) exhibited aninduction time, during which no measurable amount of drug was released.In addition, during steady state release (constant Δƒ/Δ t), differentdrugs exhibited different release rates. As a result, variation wasobserved in both the rate of steady state release and the overall periodof time over which the drug is released. Visual observations confirmedthat pellets containing different drugs dissolved at different rates,and become invisible to the naked eye after different periods of timethat correlated to the time at which ƒ≈1 as measured by UV Spectroscopy.Thus, drug release rate of the polymers can be characterized by twoglobal parameters: The delay period (i.e. the time required to reach thesteady state release rate) and the steady state release rate.

The same polymer was utilized in each of the above matrices. Thus, thedifferences in the delay period and steady state release rates of thematrices were due to the drug component of the matrix. Differences inthe release rate of a drug matrix may attributed to different diffusionand leaching rates of the drugs within the polymeric matrix, and/or todifferent polymer degradation rates. Polymer degradation rates varyamong the matrices utilized in this experiment, as evidenced bydifferent rates of disappearance of the pellets. Thus, the presence ofthe drug affects the polymer degradation rate.

To understand the effect of an incorporated drug on the polymerdegradation, the following model of the degradation process wasdeveloped, based on the data of the present invention: The mobility(diffusion) of the drug in the polymeric matrix is likely to benegligible compared to the polymer degradation rate. Thus, drug releaseoccurs chiefly via polymer degradation. The polymer PLGA degradationinto lactic acid and glycolic acid occurs through a reaction with water:(C₃H₄O₂)_(x)(C₂H₂O₂)_(y)+2H₂O→CH₃CROHCOOH+HCHOHCOOH.

Thus, the rate of degradation depends on the availability of watermolecules. In systems where the diffusion of water into the pellet issuppressed, this indicates surface erosion. In systems where thediffusivity of water into the polymer is high, this leads to bulkerosion.

The degradation reaction is likely to be a 1^(st) order reaction betweenthe polymer and water, and is thus proportional to the localconcentration of both species. However, since the polymer comprises themajority of the pellet, its concentration is fixed everywhere. Thus, thedegradation reaction is proportional to the local concentration of water(a function of the diffusivity) times a constant. Defining the diffusioncoefficient of water into the polymer pellet as D, thediffusion/reaction equation for water is written as (1):

$\begin{matrix}{\frac{\partial c_{w}}{\partial t} = {{D{\nabla^{2}c_{w}}} - {kc}_{w}}} & (1)\end{matrix}$where k the reaction rate, which includes the local polymerconcentration, is constant. Appropriate boundary conditions are that theconcentration of water at the particle edge is fixed by the solutionvalue c_(w) ⁰, and that initially (at t=0) the concentration of water inthe particle is zero.

Equation (1) indicates that in systems where D is close to 0, there isno diffusion into the polymeric particle, c_(w) is zero within thepellet, and all reactions take place at the polymer/solution interface.In systems where the diffusion rate is large compared to the reactionrate, water will penetrate and degrade the entire particle volumethrough bulk erosion. The water concentration profile is solved byassuming that the pellet is a semi-infinite medium. This assumption isappropriate for the initial and steady-state stages of the degradationwhen the diffusion distance of the water is small compared to pelletdimensions.

Defining the distance from the polymer/solution interface as x, it wasfound that:

$\begin{matrix}{\frac{c_{w}}{c_{w}^{0}} = {{{\mathbb{e}}^{- {kt}}\left( {1 - {{erf}\left\lbrack \frac{x}{\sqrt{Dt}} \right\rbrack}} \right)} + {k{\int_{0}^{t}{{{\mathbb{e}}^{- {kt}^{\prime}}\left( {1 - {{erf}\left\lbrack \frac{x}{\sqrt{{Dt}^{\prime}}} \right\rbrack}} \right)}\ {\mathbb{d}t^{\prime}}}}}}} & (2)\end{matrix}$

The amount of polymer that reacted, at any given location (x), withwater and degraded was then obtained through integration over time:

$\begin{matrix}{{{dM}_{p}\left( {x,t} \right)} = {k{\int_{0}^{t}{{c_{w}\left( {x,t^{\prime}} \right)}\ {\mathbb{d}t^{\prime}}}}}} & \left( {3.a} \right)\end{matrix}$where dM_(p) (x,t) is the change in polymer pellet mass at point x.Thus, the overall mass of degraded polymer is described by

$\begin{matrix}{{\Delta\; M_{p}} = {{\int_{x = 0}^{\infty}{{{dM}_{p}\left( {x,t} \right)}\ {\mathbb{d}x}}} = {k{\int_{x = 0}^{\infty}{\int_{0}^{t}{{c_{w}\left( {x,t^{\prime}} \right)}\ {\mathbb{d}t^{\prime}}\ {\mathbb{d}x}}}}}}} & \left( {3.b} \right)\end{matrix}$and the amount of released drug M_(d) (neglecting drug diffusion) is

$\begin{matrix}{{M_{d}(t)} = {{\phi\;{dM}_{p}} = {\phi\; k{\int_{0}^{\infty}{\int_{0}^{t}{{c_{w}\left( {x,t^{\prime}} \right)}\ {\mathbb{d}t^{\prime}}\ {\mathbb{d}x}}}}}}} & (4)\end{matrix}$where φ is the weight fraction of the drug in the particle. Initially,when t is small, M_(d) is described by

$\begin{matrix}{M_{d} \approx \frac{2\phi\; c_{w}^{0}D^{1/2}t^{3/2}}{3\pi^{1/2}} \sim t^{3/2}} & \left( {5.a} \right)\end{matrix}$while at later time points, the release rate is given by

$\begin{matrix}{M_{d} \approx \frac{\phi\; c_{w}^{0}D^{1/2}t}{2k^{1/2}} \sim t} & \left( {5.b} \right)\end{matrix}$

It was thus determined that, initially, the amount of drug releasedincreases with time to the power of (3/2), with a release rate (theslope) that is dependent only upon the water diffusion coefficient D. Astime increases, the amount of released drug becomes linear with time. Inthis regime the system reaches “steady state” when the degradation rateand the amount of drug released are constant with time. Accordingly, therelease rate varies with the ratio between the diffusion and reactionconstants.

The model described by Equation (4) fit well the drug release data shownin FIG. 10 for all six drugs tested, with values of D and k as listed inTable 2 (the curves for haloperidol and aspirin are depicted in FIG.11). This is notable because the drugs tested are diverse; e.g.haloperidol and aspirin are very different. The deviations seen at latetime points arose from the finite size of the pellets.

Thus, the release rate of drugs from biodegradable matrices can beaccounted for by a model containing only two fit parameters: D and k.

Example 11 Parameters D and K in the Release Equation can be Determinedfrom the Solubility of the Drug and Its Density of Hydroxyl Groups

It was observed that the parameter k, the coefficient for thedegradation reaction, varied over less than an order of magnitude forall drugs (0.05-0.33); by contrast, D, the diffusion coefficient, variedover 8 orders of magnitude (Table 2).

The diffusion constant of molecules in solid polymeric media isdescribed by D₀ e sup[-δε], where D₀ is a proportionality coefficient, εis an activation, or interaction energy and δ is a thermodynamicconstant that depends, among other things, on the system temperature. Inthe present case, the polymeric matrix is the same, as is thetemperature; thus, D₀ and δ are the same for all polymer/drug pellets.The activation energy ε, however, is sensitive to the specificinteractions between the diffusant and the matrix, and thus varies withdrug type and loading (mass fraction). The drug solubility in water(assuming an ideal mixture) can also be described in terms of ε: S, thesolubility, is equal to S₀e-sup[-δε], where S₀ is a proportionalitycoefficient and σ is a thermodynamic constant. Combining therelationships for D and S leads to the following relationship:D=(D ₀ S ₀ ^(δ/σ))S ^(δ/σ)  (6)wherein the term in parenthesis is, in the present case, a systemconstant.

As depicted in FIG. 12, the solubility data was fit to equation (6). Thedependence of D on the solubility was described through a power law,with a coefficient of approximately 5.3.

In conclusion, the model described by Equation (4) can be used topredict the drug release rate during the steady state for PLGA implantscontaining 20% drug load. D is proportional to the solubility to thepower of 5.3, and k is a number within the range of about 0.05-0.33.

Example 12 Determination of Drug Release from PLGA Polymer Implants andResulting Serum Drug Concentration as a Function of Time and ImplantProperties

Since the focus of Examples 10-11 was to examine the effect ofdrug/polymer/water interactions on the degradation and release rate, theoriginal model utilized an implant of infinitely large size. The presentExample describes the time-dependent concentration of drug in vivo. Tothat end, the previous model was modified to account for (1) finiteimplant size and (2) drug absorption and clearance (metabolic rate). Therate of drug release from an implant is proportional to the implantsurface area (SA). Correcting for change in implant mass, the SA of theimplant, A, can be described as equation 7, where R(t) is the implantradius as a function of time t, R₀ is the initial radius, D is thediffusion coefficient of water into the matrix, k the reaction rate andC_(w) the concentration of water.

$\begin{matrix}{A = {{4\;\pi\;{R^{2}(t)}} = {4\;\pi\;{R_{0}^{2}\left( {1 - {\frac{C_{w}\sqrt{D}}{2R_{0}\sqrt{k}}t}} \right)}^{2}}}} & (7)\end{matrix}$

The rate of drug release per unit time can therefore be calculated asequation 8.

$\begin{matrix}{\left( \frac{\mathbb{d}M_{d}}{\mathbb{d}t} \right) = {{{A(t)}\frac{C_{w}\sqrt{D}{{erf}\left\lbrack \sqrt{kt} \right\rbrack}}{2\sqrt{k}}} = {4\;\pi\;{R_{0}^{2}\left( {1 - {\frac{C_{w}\sqrt{D}}{2R_{0}\sqrt{k}}t}} \right)}^{2}\frac{C_{w}\sqrt{D}{{erf}\left\lbrack \sqrt{kt} \right\rbrack}}{2\sqrt{k}}}}} & (8)\end{matrix}$

where “erf(x)” refers to

$\frac{2}{\sqrt{\pi}}{\int_{0}^{x}{{\mathbb{e}}^{- {t2}}\ {{\mathbb{d}t}.}}}$

The metabolic rate of risperidone can be written as an exponential decayof drug in blood, with a characteristic decay rate r that varies as afunction of drug and metabolic rate, yielding a complex function for theeffective drug concentration shown in equation 9. The function can beasymmetric, and its degree of asymmetry is set by the value of τ, thetypical metabolizing time for the given drug. A high value of τindicates slow metabolic rate, and thus the function is moresymmetrical. A low value of τ indicates fast metabolism and the functionbecomes more asymmetric as the peak moves closer to t=0.

$\begin{matrix}{\left( \frac{\mathbb{d}M_{d}}{\mathbb{d}t} \right) = {4\;\pi\;{R_{0}^{2}\left( {1 - {\frac{C_{w}\sqrt{D}}{2R_{0}\sqrt{k}}t}} \right)}^{2}\frac{C_{w}\sqrt{D}{{erf}\left\lbrack \sqrt{kt} \right\rbrack}}{2\sqrt{k}}\left( {1 - {\mathbb{e}}^{t/\tau}} \right)}} & (9)\end{matrix}$

The concentration of drug as a function of time is a complex function.The error function can be approximated as erf(x)˜1-e^(−7x/4), yieldingequation 10 for the drug concentration. a₁ is a constant equal to thetotal drug content of the implant, variable a₂ is a constant equal tothe metabolic rate, variable a₃ reflects diffusion of drug from theimplant and variable a₄ reflects polymer degradation and influencestotal release interval. Fitting rabbit haloperidol data, we extract thecoefficient τ=0.027, indicating a serum half-life for haloperidol inrabbit of about 130 minutes, consistent with published data (WurzburgerR J, Miller R L et al, J Pharmacol Exp Ther 217: 757-763). This equationfits prior in vivo rabbit data with a correlation coefficient (R²) of0.87.

$\begin{matrix}{\left( \frac{\mathbb{d}M_{d}}{\mathbb{d}t} \right) \sim {{a_{1}\left( {1 - {\mathbb{e}}^{{- \alpha_{2}}t}} \right)}\left( {1 + {\mathbb{e}}^{\alpha_{3}\sqrt{t}}} \right)\left( {1 - {a_{4}t}} \right)^{2}}} & (10)\end{matrix}$

Example 13 Determination of the Contribution of Polymer Composition andInherent Viscosity on Drug Release from PLGA Polymer Implants

Polymer composition and inherent viscosity are varied as described inExamples 1-7 to determine the additional contributions of thesevariables to drug release from PLGA polymer implants. Additionalequations are produced, incorporating these variables.

Example 14 Scaling-Up of Risperidone Implants to Human Subjects

Considerable interspecies differences exist in the metabolism ofrisperidone, with both rabbits and monkeys requiring approximately 15 to30 fold higher doses than humans for equivalent plasma concentrations(Bacopoulos N G, Redmond D E, et al, J Pharmacol Exp Ther 212: 1-5;Jibiki I, Kubota T, et al, Jpn J Psychiatry Neurol 47: 627-629;Klintenberg R, Gunne L, Andren P E (2002) Mov Disord 17: 360-365). Thus,the absolute doses used in the above animal studies approximate theamount of drug needed for a human, despite the difference in body mass.Since humans require approximately 1 mg/kg/month of risperidone(typically about 1.8 mg/day) when administered as a depot preparation,an implant system containing 600 mg would provide one year of treatmentfor a 50 kg patient. Thus, the implant design used in the animal studiesnecessitates about 1.5 grams of material with 40% drug load for one yearof risperidone. At a density of 1.2 g per cc and diameter of 3.6 mm,this requires approximately 6.5 cm of implant rods.

Risperidone implants within the following parameters are administered tohumans:

drug load between about 30%-60%, inclusive.

PLA:PGA molar ratio between about 50:50 and 100:0, inclusive.

Rod-shaped.

SA:V ratio between 1.5 and 2.

For example, rod-shaped implants with length between about 3-5 mm,inclusive and diameter between 2 and 3.6 mm, inclusive, exhibit thetarget SA:V ratio. By administration of 1 or more implants, asubstantially symmetrical concentration profile is achieved, as seen inExample 2, with peak levels reached at approximately 6 months andtherapeutic risperidone levels achieved between 2 and 8 months postimplantation (FIG. 13A).

Example 15 Cyclical Administration or Risperidone Implants AchievesLong-Term Therapeutic Risperidone Levels

The symmetrical release profile described in Example 14 is used toprovide long-term therapeutic drug levels by introducing a new set ofimplants approximately every 6 months (FIG. 13B). For example, two rodsof 3.2 cm length with 100% PLA are administered every 6 months. Asdepicted, each subsequent set of implants increases medication levels atthe same rate that the contribution from the previous set is declining,such that the overall rate of release remains approximately constant(FIG. 13C).

Example 16 Improvement of Initial Drug Levels by Inclusion ofFaster-Release Polymers in the Initial Implantation

A limitation of a single-polymer system is a lag in reaching therapeuticlevels following the initial implantation. Thus, additional implantsthat provide a more rapid time to peak concentration are included in theinitial implantation. One or more of the implants depicted in Table 4 isincluded. Release rates of the rapid-release implants in Table 4 andresulting serum concentrations are derived from equations 8-10 byvarying the parameters a1 and a4, which are related to drug content(total dose) and polymer degradation (PLGA ratio and inherentviscosity).

TABLE 4 Additional polymer implants utilized with initial implantation.Implants contain between 40-60% risperidone load, inclusive, and exhibita target delivery of 0.15 mg/day. Each rod has a 3.6 mm diameter withdensity of 1.2 grams per cubic centimeter (g/cc), yielding rods withapproximately 125 mg/cm of implant. mg total cm implant Days to Days toimplant mass length maximum full 0%, 40%, 50%, 0%, 40%, 50%, Polymerconcentration release 60% 60% 50:50 L 20 40 60, 60, 48, 40 0.5, 0.5,0.4, 0.3 50:50 H 28 55 83, 83, 66, 55 0.6, 0.6, 0.5, 0.4 65:35 L 45 90135, 135, 108, 1.1, 1.1, 0.8, 0.7 90 65:35 H 55 110 165, 165, 132, 1.1,1.4, 1.1, 0.9 110 75:25 L 60 120 180, 180, 144, 1.5, 1.5, 1.2, 1.0 12075:25 H 70 140 210, 210, 168, 1.7, 1.7, 1.3, 1.1 140 85:15 L 75 150 225,225, 180, 1.8, 1.8, 1.4, 1.2 150 85:15 H 90 180 270, 270, 216, 2.1, 2.1,1.7, 1.4 180 100:0 L  175 350 525, 525, 420, 4.2, 4.2, 3.4, 2.8 350100:0 H  190 380 570, 570, 456, 4.5, 4.5, 3.6, 3.0 380 Positive ControlsDays of exposure = 30, 60, 90, 120, 180, 360

For example, FIG. 14A illustrates the drug release from fourrapid-release implants having half-lives of approximately 2, 4, 8 and 12weeks and full release intervals of approximately 4, 8, 16 and 24 weeks,respectively. For example, a set of implants containing half of thefirst 6 months of medication includes 4 implants with an average lengthof 0.8 cm, composed of 50:50, 65:35, 75:25 and 85:15 PLGA respectively.This set is given in combination with the slower-release implants, whichprovides the other half of the medication. When this combination ofimplants is administered at the first implantation, therapeutic druglevels are attained within a few days of implantation, and are sustainedindefinitely via implantation of the slower-release implants at 6-monthintervals thereafter (FIG. 14B).

1. An implantable, long term delivery system for improving medicationadherence in disorders associated with a likelihood of non-compliance,comprising: a therapeutic drug in an implantable, rod-shaped structure,wherein said rod-shaped structure is degradable and further comprises apolymer, said polymer comprising polylactic acid (PLA) and polyglycolicacid (PGA) in a PLA:PGA molar ratio from 50:50 to 100:0, wherein saidtherapeutic drug in said rod-shaped structure is capable of exhibitingthe time to maximum serum concentration ranging from about 20 days toabout 190 days after implanting said system in a subject, and whereinsaid therapeutic drug is risperidone, 9-OH-risperidone, or an activemetabolite thereof.
 2. The implantable, long term delivery system ofclaim 1, wherein said rod-shaped structure is removable.
 3. Theimplantable, long term delivery system of claim 1, wherein said implanthas a surface area to volume ratio between 0.6 and 6 (millimeters)/mm³.4. The implant of claim 1, wherein said implant has a length between1-45 millimeters.
 5. The implantable, long term delivery system of claim1, wherein said implant has a diameter between 2-4 millimeters.
 6. Abiodegradable, rod-shaped implant comprising a therapeutic drug and apolymer, said polymer comprising polylactic acid (PLA) and optionallypolyglycolic acid (PGA) in a PLA:PGA molar ratio between 50:50 and100:0, wherein said therapeutic drug is present in an amount of 10%-60%of the mass of said implant, and said polymer is present in an amount of40%-90% of the mass of said implant, and wherein said therapeutic drugin said rod-shaped implant is capable of exhibiting the time to maximumserum concentration ranging from about 20 days to about 190 days afterimplanting said implant in a subject, and wherein said therapeutic drugis risperidone, 9-OH-risperidone, or an active metabolite thereof. 7.The implant of claim 6, wherein said implant is removable.
 8. Theimplant of claim 6, wherein said PLA:PGA molar ratio is between 75:25and 100:0.
 9. The implant of claim 6, wherein said therapeutic drug isan anti-psychotic agent.
 10. The implant of claim 6, wherein saidimplant has a surface area to volume ratio between 1 and 4(millimeters)/mm³.
 11. The implant of claim 6, wherein said implant hasa length between 3-45 millimeters.
 12. The implant of claim 6, whereinsaid implant has a diameter between 2-4 millimeters.
 13. A method fortreating a subject for a disorder associated with a likelihood ofnon-compliance, comprising administering to said subject a therapeuticdrug in a long term delivery system, wherein said long term deliverysystem comprises an implantable, rod-shaped structure, said implantable,rod-shaped structure comprising the target therapeutic drug and apolymer, said polymer comprising polylactic acid (PLA) and optionallypolyglycolic acid (PGA) in a PLA:PGA molar ratio between 50:50 and100:0, wherein said therapeutic drug in said rod-shaped implant iscapable of exhibiting the time to maximum serum concentration rangingfrom about 20 days to about 190 days after implanting said system in asubject, and wherein said therapeutic drug is risperidone,9-OH-risperidone, or an active metabolite thereof, thereby treating saidsubject for said disorder associated with a likelihood ofnon-compliance.
 14. The method of claim 13, wherein said step ofadministering is reversible.
 15. The method of claim 13, wherein saidPLA:PGA molar ratio is between 85:15 and 100:0.
 16. The method of claim13, wherein said rod-shaped structure has a surface area to volume ratiobetween 1 and 3 (millimeters)/mm³.
 17. The method of claim 13, whereinsaid long term delivery system further comprises a starter set of one ormore different biodegradable rod-shaped structures, wherein saiddifferent biodegradable rod-shaped structures differ from theimplantable, rod-shaped structure of claim 13 in drug load, PLA:PGAratio, surface area to volume ratio, mass, length, diameter, or inherentviscosity, and whereby said different rod-shaped structures reachsteady-state levels of drug release faster than the implantable,rod-shaped structure of claim
 13. 18. The method of claim 17, whereinsaid one or more different biodegradable rod-shaped structures, if morethan one in number, differ substantially from one another in saidPLA:PGA molar ratio.
 19. A method for treating a schizophrenia in ahuman, comprising performing the method of claim 13 on said human,thereby treating a schizophrenia in a human.
 20. The implantable, longterm delivery system of claim 1, wherein said therapeutic drug ispresent in an amount of 10%-60% of the mass of said system.
 21. Theimplantable, long term delivery system of claim 1, wherein said polymeris present in an amount of 40%-80% of the mass of said system.
 22. Theimplantable, long term delivery system of claim 1, wherein said polymercomprises PLA and PGA in a PLA:PGA molar ratio of 60:40.
 23. Theimplantable, long term delivery system of claim 1, wherein said polymercomprises PLA and PGA in a PLA:PGA molar ratio of 75:25.
 24. Theimplantable, long term delivery system of claim 1, wherein said polymercomprises PLA and PGA in a PLA:PGA molar ratio of 85:15.
 25. Theimplantable, long term delivery system of claim 1, wherein said polymercomprises PLA and PGA in a PLA:PGA molar ratio of 90:10.
 26. Theimplantable, long term delivery system of claim 1, wherein saidtherapeutic drug is present in an amount of 30%-60% of the mass of saidsystem.
 27. The implantable, long term delivery system of claim 1,wherein said therapeutic drug is present in an amount of 40%-50% of themass of said system.
 28. The implantable, long term delivery system ofclaim 1, wherein said polymer is present in an amount of 40%-70% of themass of said system.
 29. The implantable, long term delivery system ofclaim 1, wherein said polymer is present in an amount of 50%-60% of themass of said system.